Dihydropyrrolopyridine inhibitors of ROR-gamma

ABSTRACT

Provided are novel compounds of Formula (I): 
                         
pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof, which are useful in the treatment of diseases and disorders mediated by RORγ. Also provided are pharmaceutical compositions comprising the novel compounds of Formula (I) and methods for their use in treating one or more inflammatory, metabolic, autoimmune and other diseases or disorders.

RELATED APPLICATIONS

This application is a continuation of International Application No.PCT/US2015/055420, filed Oct. 14, 2015, which claims the benefit of thefiling date of U.S. Provisional Application No. 62/063,912, filed Oct.14, 2014 and U.S. Provisional Application No. 62/074,406, filed Nov. 3,2014. The entire contents of the aforementioned applications areincorporated herein by reference.

TECHNICAL FIELD OF THE INVENTION

The present invention is directed to novel retinoic acidreceptor-related orphan receptor gamma (“ROR

” or “ROR-gamma”) inhibitors, processes for their preparation,pharmaceutical compositions containing these inhibitors, and their usein the treatment of inflammatory, metabolic, autoimmune and otherdiseases mediated by ROR

.

BACKGROUND OF THE INVENTION

Retinoic acid receptor-related orphan receptors (RORs) are a subfamilyof transcription factors in the steroid hormone nuclear receptorsuperfamily (Jetten & Joo (2006) Adv. Dev. Biol. 2006, 16, 313-355). TheROR family consists of ROR alpha (RORα), ROR beta (RORβ) and ROR gamma(ROR

), each encoded by a separate gene (in human: RORA, RORB and RORC,respectively; in mouse: rora, rorb and rorc, respectively). RORs containfour principal domains shared by the majority of nuclear receptors: anN-terminal domain, a highly conserved DNA-binding domain (DBD)consisting of two zinc finger motifs, a hinge domain, and a ligandbinding domain (LBD). Each ROR gene generates several isoforms,differing only in their N-terminal domains. ROR

has two isoforms: ROR

1 and ROR

2 (also known as ROR

t). ROR

refers to ROR

1 and/or ROR

t. ROR

1 is expressed in a variety of tissues including thymus, muscle, kidneyand liver, but ROR

t is exclusively expressed in the cells of the immune system, has acritical role in thymopoiesis and the development of several secondarylymphoid tissues, and is a key regulator of Th17 cell differentiation(Jetten, 2009, Nucl. Recept. Signal., 7:e003, doi:10.1621/nrs.07003,Epub 2009 Apr. 3).

Th17 cells are a subset of T helper cells which preferentially producethe pro-inflammatory cytokines IL-17A, IL-17F, IL-21 and IL-22. Th17cells and their effector molecules, such as IL-17, IL-21, IL-22, GM-CSFand CCL20, are associated with the pathogenesis of several autoimmuneand inflammatory diseases, such as rheumatoid arthritis, systemic lupuserythematosus, multiple sclerosis, psoriasis, inflammatory boweldisease, allergy and asthma (Maddur et al., 2012, Am. J. Pathol.,181:8-18). Recent findings support a role for IL17 and Th17 cells in thepathogenesis of acne (Thiboutot et al., 2014, J. Invest. Dermatol.,134(2):307-10, doi: 10.1038/jid.2013.400; Agak et al., 2014, J. Invest.Dermatol., 134(2):366-73, doi: 10.1038/jid.2013.334, Epub 2013 Aug. 7).Th17 cells are also potent inducers of inflammation associated withendometriosis, a chronic inflammatory disease (Hirata et al., 2010,Endocrinol., 151:5468-5476; Hirata et al., 2011, Fertil Steril., July;96(1):113-7, doi: 10.1016/j.fertnstert.2011.04.060, Epub 2011 May 20).Additionally, Th17 cells have a key role in the mouse autoimmune modelsof experimental autoimmune encephalomyelitis (EAE), collagen-inducedarthritis (CIA) and adjuvant-induced arthritis (AIA) (Bedoya et al.,2013, Clin. Dev. Immunol., 2013:986789. Epub 2013 Dec. 26. Th17 cellsare activated during inflammatory and autoimmune disease processes andare responsible for recruiting other inflammatory cell types,particularly neutrophils, to mediate pathology in target tissues(Miossec & Kolls, 2012, Nature Rev., 11:763-776; Korn et al., 2009,Annu. Rev. Immunol., 27:485-517). Aberrant Th17 cell function has beenimplicated in a variety of autoimmune diseases, including multiplesclerosis and rheumatoid arthritis. Autoimmune disease is believed toarise from the disruption of the equilibrium between effector andregulatory T cells (Solt et al., 2012, ACS Chem. Biol., 7:1515-1519,Epub 2012 Jul. 9). The importance of ROR

t to Th17 cell differentiation and the pathogenic role of Th17 cells isevidenced by the fact that ROR

t-deficient mice have very few Th17 cells and have a reduction inseverity of EAE (Ivanov et al., 2006, Cell, 126:1121-1133).

Circadian rhythms are daily cycles of behavioral and physiologicalchanges that are regulated by endogenous circadian clocks. A number ofstudies have established links between nuclear receptor (including ROR

) function and expression, the circadian regulatory circuitry, and theregulation of various physiological processes (Jetten (2009) op. cit.).

Obstructive sleep apnea syndrome (OSAS) is a chronic inflammatorydisease regulated by T lymphocytes. OSAS patients have a significantincrease in peripheral Th17 cell frequency, IL-17 and ROR

t levels (Ye et al., 2012, Mediators Inflamm., 815308, doi:10.1155/2012/815308, Epub 2012 Dec. 31).

A number of studies have provided evidence of a role of RORs in cancer.Mice deficient in the expression of ROR

exhibit a high incidence of thymic lymphomas that metastasize frequentlyto liver and spleen. High expression of Th17-associated genes (includingROR

) and high levels of Th17 cells in the tumor microenvironment has beenshown to correlate with a poor prognosis in various cancers, includinglung, gastric, breast and colon cancer (Tosolini et al., 2011, CancerRes., 71:1263-1271, doi: 10.1158/0008-5472.CAN-10-2907, Epub 2011 Feb.8; Su et al., 2014, Immunol. Res., 58:118-124, doi:10.1007/s12026-013-8483-y, Epub 2014 Jan. 9; Carmi et al., 2011, J.Immunol., 186:3462-3471, doi: 10.4049/jimmunol.1002901, Epub 2011 Feb.7; Chen et al., 2013, Histopathology, 63:225-233, doi:10.1111/his.12156, Epub 2013 Jun. 6).

ROR

has also been identified to have a regulatory role in lipid/glucosehomeostasis, and has been implicated in metabolic syndrome, obesity(Meissburger et al., 2011, EMBO Mol. Med., 3:637-651), hepatosteatosis,insulin resistance and diabetes.

Further support for the role of ROR

in the pathogenesis of inflammatory, metabolic, circadian effect,cancer, and autoimmune diseases and disorders can be found in thefollowing references: Chang et al., 2012, J. Exp. Pharmacol., 4:141-148;Jetten et al., 2013, Frontiers Endocrinol., 4:1-8; Huh & Littman, 2012,Eur. J. Immunol., 42:2232-2237; Martinez et al., 2008, Ann. N.Y. Acad.Sci., 1143:188-211; Pantelyushin et al., 2012, J. Clin. Invest.,122:2252-2256; Jetten & Ueda, 2002, Cell Death Differen., 9:1167-1171;Solt et al., 2010, Curr. Opin. Lipidol., 21:204-211.

In light of the role that ROR

plays in disease pathogenesis, inhibition of ROR

activity and Th17 cell differentiation and activity, including IL17production, will be of significant therapeutic benefit. It is thereforedesirable to prepare compounds that inhibit ROR

activity and hence have utility in the treatment of inflammatory,autoimmune, metabolic, circadian effect, cancer, and other diseasesmediated by ROR

, such as e.g., asthma, atopic dermatitis, acne, Crohn's disease,regional enteritis, ulcerative colitis, Sjögren's syndrome, uveitis, Beh

et's disease, dermatomyositis, multiple sclerosis, ankylosingspondylitis, systemic lupus erythematosus, scleroderma, psoriasis,psoriatic arthritis, steroid resistant asthma and rheumatoid arthritis.

SUMMARY OF THE INVENTION

It has now been found that compounds described herein, andpharmaceutically acceptable compositions thereof, are effectiveinhibitors of ROR

(see e.g., Table 2). Such compounds include those of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein each of R², R³,R⁴, Cy¹, and Cy² are as defined and described herein.

The provided compounds, and pharmaceutically acceptable compositionsthereof, are inverse agonists or antagonists of ROR

and are useful for treating a variety of diseases, disorders orconditions. Such diseases, disorders, or conditions include thosedescribed herein.

The provided compounds can be used alone (i.e., as a monotherapy) or incombination with one or more other therapeutic agent effective fortreating any of the indications described herein.

Compounds provided herein possess the technical advantage of havingtherapeutic relevance in cell-free competition assays, cell-basedtranscriptional assays, whole blood assays, and hERG potassium channelassays, e.g., see Tables 2 and 3 below.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 depicts the powder X-ray diffractogram of(S)-7-ethyl-N—((R)-1-(4-(ethylsulfonyl)phenyl)-2-hydroxyethyl)-6-((trans-4-(trifluoromethyl)cyclohexyl)methyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-3-carboxamidemesylate.

DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS 1. General Description ofCompounds of the Invention

In certain embodiments, the present invention provides a compound ofFormula (I):

or a pharmaceutically acceptable salt thereof, wherein:

R² is (C₁-C₃)alkyl, hydroxy(C₁-C₃)alkyl, halo(C₁-C₃)alkyl, benzyl,(C₁-C₃)alkoxy(C₁-C₃)alkyl, tetrahydropyranyl, or —CH₂-tetrahydropyranyl;

R³ and R⁴ are each independently hydrogen or methyl;

Cy¹ is phenyl or pyridyl, each substituted with (C₁-C₃)alkylsulfonyl;and

Cy² is hydrogen, halo(C₁-C₃)alkyl, cyclohexyl, or tetrahydropyranyl,wherein the cyclohexyl and tetrahydropyranyl are each optionallysubstituted with one or more groups selected from halo(C₁-C₃)alkyl andC₁-C₃(alkoxy).

2. Compounds and Definitions

The terms “halo” and “halogen” as used herein refer to an atom selectedfrom fluorine (fluoro, —F), chlorine (chloro, —Cl), bromine (bromo,—Br), and iodine (iodo, —I).

The term “alkyl”, used alone or as a part of a larger moiety such ase.g., “haloalkyl”, means a saturated monovalent straight or branchedhydrocarbon radical having, unless otherwise specified, 1-6 carbon atomsand includes, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl,sec-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl,n-nonyl, n-decyl and the like. “Monovalent” means attached to the restof the molecule at one point.

The term “haloalkyl” or “halocycloalkyl” include mono, poly, andperhaloalkyl groups where the halogens are independently selected fromfluorine, chlorine, iodine, and bromine.

As used herein the terms “subject” and “patient” may be usedinterchangeably, and means a mammal in need of treatment, e.g.,companion animals (e.g., dogs, cats, and the like), farm animals (e.g.,cows, pigs, horses, sheep, goats and the like) and laboratory animals(e.g., rats, mice, guinea pigs and the like). Typically, the subject isa human in need of treatment.

Certain of the disclosed compounds may exist in various stereoisomericforms. Stereoisomers are compounds that differ only in their spatialarrangement. Enantiomers are pairs of stereoisomers whose mirror imagesare not superimposable, most commonly because they contain anasymmetrically substituted carbon atom that acts as a chiral center.“Enantiomer” means one of a pair of molecules that are mirror images ofeach other and are not superimposable. Diastereomers are stereoisomersthat contain two or more asymmetrically substituted carbon atoms. Thesymbol “*” in a structural formula represents the presence of a chiralcarbon center. “R” and “S” represent the configuration of substituentsaround one or more chiral carbon atoms. Thus, “R*” and “S*” denote therelative configurations of substituents around one or more chiral carbonatoms.

“Racemate” or “racemic mixture” means a compound of equimolar quantitiesof two enantiomers, wherein such mixtures exhibit no optical activity,i.e., they do not rotate the plane of polarized light.

“Geometric isomer” means isomers that differ in the orientation ofsubstituent atoms in relationship to a carbon-carbon double bond, to acycloalkyl ring, or to a bridged bicyclic system. Atoms (other than H)on each side of a carbon-carbon double bond may be in an E (substituentsare on opposite sides of the carbon-carbon double bond) or Z(substituents are oriented on the same side) configuration. “R,” “S,”“S*,” “R*,” “E,” “Z,” “cis,” and “trans,” indicate configurationsrelative to the core molecule. When a disclosed compound is named ordepicted by structure without indicating a particular geometric isomerform, it is to be understood that the name or structure encompasses onegeometric isomer free of other geometric isomers, mixtures of geometricisomers, or all geometric isomers.

The compounds of the invention may be prepared as individual enantiomersby either enantio-specific synthesis or resolved from anenantiomerically enriched mixture. Conventional resolution techniquesinclude forming the salt of a free base of each isomer of anenantiomeric pair using an optically active acid (followed by fractionalcrystallization and regeneration of the free base), forming the salt ofthe acid form of each enantiomer of an enantiomeric pair using anoptically active amine (followed by fractional crystallization andregeneration of the free acid), forming an ester or amide of each of theenantiomers of an enantiomeric pair using an optically pure acid, amineor alcohol (followed by chromatographic separation and removal of thechiral auxiliary), or resolving an enantiomeric mixture of either astarting material or a final product using various well knownchromatographic methods.

When the stereochemistry of a disclosed compound is named or depicted bystructure, the named or depicted stereoisomer is at least 60%, 70%, 80%,90%, 99% or 99.9% by weight pure relative to all of the otherstereoisomers. Percent by weight pure relative to all of the otherstereoisomers is the ratio of the weight of one stereoisomer over theweight of the other stereoisomers. When a single enantiomer is named ordepicted by structure, the depicted or named enantiomer is at least 60%,70%, 80%, 90%, 99% or 99.9% by weight optically pure. Percent opticalpurity by weight is the ratio of the weight of the enantiomer over theweight of the enantiomer plus the weight of its optical isomer.

When the stereochemistry of a disclosed compound is named or depicted bystructure, and the named or depicted structure encompasses more than onestereoisomer (e.g., as in a diastereomeric pair), it is to be understoodthat one of the encompassed stereoisomers or any mixture of theencompassed stereoisomers are included. It is to be further understoodthat the stereoisomeric purity of the named or depicted stereoisomers atleast 60%, 70%, 80%, 90%, 99% or 99.9% by weight pure relative to all ofthe other stereoisomers. The stereoisomeric purity in this case isdetermined by dividing the total weight in the mixture of thestereoisomers encompassed by the name or structure by the total weightin the mixture of all of the stereoisomers.

When a disclosed compound is named or depicted by structure withoutindicating the stereochemistry, and the compound has one chiral center,it is to be understood that the name or structure encompasses oneenantiomer of compound free from the corresponding optical isomer, aracemic mixture of the compound and mixtures enriched in one enantiomerrelative to its corresponding optical isomer.

When a disclosed compound is named or depicted by structure withoutindicating the stereochemistry and has at least two chiral centers, itis to be understood that the name or structure encompasses onestereoisomer free of other diastereomers, mixtures of stereoisomers, andmixtures of stereoisomers in which one or more diastereomers is enrichedrelative to the other diastereomer(s).

The compounds of the invention may be present in the form ofpharmaceutically acceptable salts. For use in medicines, the salts ofthe compounds of the invention refer to non-toxic “pharmaceuticallyacceptable salts.” Pharmaceutically acceptable salt forms includepharmaceutically acceptable acidic/anionic or basic/cationic salts.

Pharmaceutically acceptable basic/cationic salts include, the sodium,potassium, calcium, magnesium, diethanolamine, n-methyl-D-glucamine,L-lysine, L-arginine, ammonium, ethanolamine, piperazine andtriethanolamine salts.

Pharmaceutically acceptable acidic/anionic salts include, e.g., theacetate, benzenesulfonate, benzoate, bicarbonate, bitartrate, carbonate,citrate, dihydrochloride, gluconate, glutamate, glycollylarsanilate,hexylresorcinate, hydrobromide, hydrochloride, malate, maleate,malonate, mesylate, nitrate, salicylate, stearate, succinate, sulfate,tartrate, and tosylate.

3. Description of Exemplary Compounds

In a first embodiment, the present invention provides a compound ofFormula (I),

or a pharmaceutically acceptable salt thereof, wherein the variables areas described above.

In a second embodiment, the compound of Formula (I) is of Formula (II):

or a pharmaceutically acceptable salt thereof, wherein the variables instructural Formula (II) are as described for Formula (I).

In a third embodiment, the compound of Formula (I) is of Formula (III):

or a pharmaceutically acceptable salt thereof, wherein the variables instructural Formula (III) are as described for Formula (I).

In a fourth embodiment, the compound of Formula (I) is of Formula (IV):

or a pharmaceutically acceptable salt thereof, wherein the variables instructural Formula (IV) are as described for Formula (I).

In a fifth embodiment, Cy² in Formulas (I) to (IV) is cyclohexyl ortetrahydropyranyl, each of which are optionally substituted with one ormore groups selected from halo(C₁-C₃)alkyl and C₁-C₃(alkoxy).

In a sixth embodiment, the compound of Formula (I) is of Formula (V):

or a pharmaceutically acceptable salt thereof, wherein X is CH or N, Y¹is O and Y² is CH₂, Y¹ is CH₂ and Y² is O, or Y¹ and Y² are each CH₂; R⁹is halo(C₁-C₃)alkyl; and R¹⁰ is (C₁-C₃)alkylsulfonyl, wherein theremaining variables are as described for Formula (I) or the fifthembodiment.

In a seventh embodiment, the compound of Formula (I) is of Formula (VI):

or a pharmaceutically acceptable salt thereof, wherein the variables instructural Formula (VI) are as described for Formula (I), or the fifthor sixth embodiment.

In an eighth embodiment, the compound of Formula (I) is of Formula(VII):

or a pharmaceutically acceptable salt thereof, wherein the variables instructural Formula (VII) are as described for Formula (I), or the fifthor sixth embodiment.

In a ninth embodiment, R² in Formulas (I) to (VII) is methyl, ethyl,benzyl, or isopropyl, wherein the remainder of the variables are asdescribed in Formula (I), or the fifth or sixth embodiment.Alternatively, R² in Formulas (I) to (VII) is ethyl or isopropyl,wherein the remainder of the variables are as described in Formula (I),or the fifth or sixth embodiment.

In a tenth embodiment, R⁹ in Formulas (V) and (VII) is CF₃ and R¹⁰ isSO₂Et or SO₂Me, wherein the remainder of the variables are as describedin Formula (I), or the fifth, sixth, or ninth embodiment.

Specific examples of compounds of the invention are provided in theEXEMPLIFICATION. Pharmaceutically acceptable salts as well as theneutral forms of these compounds are included in the invention.

In certain embodiments, the present invention provides any one of thecompounds in the foregoing examples, or a pharmaceutically acceptablesalt thereof.

In certain embodiments, the present invention provides a method oftreating a patient (e.g., a human) with a disorder mediated by ROR

comprising the step of administering to the patient an effective amountof the compound with any compound described herein, or apharmaceutically acceptable salt or composition thereof.

4. Uses, Formulation and Administration

Pharmaceutically Acceptable Compositions

According to another embodiment, the present invention provides a methodof treating a subject (e.g., a human) with a disorder mediated by ROR

using a composition comprising a compound of the invention and apharmaceutically acceptable carrier, adjuvant, or vehicle. In certainembodiments, the amount of compound of the invention in a providedcomposition is such that it is effective as an inverse agonist orantagonist to ROR

in a biological sample or in a subject. In certain embodiments, aprovided composition is formulated for administration to a subject inneed of such composition. In some embodiments, a provided composition isformulated for oral administration to a subject.

The term “pharmaceutically acceptable carrier, adjuvant, or vehicle”refers to a non-toxic carrier, adjuvant, or vehicle that does notdestroy the pharmacological activity of the compound with which it isformulated. Pharmaceutically acceptable carriers, adjuvants or vehiclesthat may be used in the compositions of this disclosure include, but arenot limited to, ion exchangers, alumina, aluminum stearate, lecithin,serum proteins, such as human serum albumin, buffer substances such asphosphates, glycine, sorbic acid, potassium sorbate, partial glyceridemixtures of saturated vegetable fatty acids, water, salts orelectrolytes, such as protamine sulfate, disodium hydrogen phosphate,potassium hydrogen phosphate, sodium chloride, zinc salts, colloidalsilica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-basedsubstances, polyethylene glycol, sodium carboxymethylcellulose,polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers,polyethylene glycol and wool fat.

Compositions described herein may be administered orally, parenterally,by inhalation spray, topically, rectally, nasally, buccally, vaginallyor via an implanted reservoir. The term “parenteral” as used hereinincludes subcutaneous, intravenous, intramuscular, intra-articular,intra-synovial, intrasternal, intrathecal, intrahepatic, intralesionaland intracranial injection or infusion techniques.

Liquid dosage forms for oral administration include, but are not limitedto, pharmaceutically acceptable emulsions, microemulsions, solutions,suspensions, syrups and elixirs. In addition to the active compounds,the liquid dosage forms may contain inert diluents commonly used in theart such as, for example, water or other solvents, solubilizing agentsand emulsifiers such as ethyl alcohol, isopropyl alcohol, ethylcarbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butylene glycol, dimethylformamide, oils (in particular,cottonseed, groundnut, corn, germ, olive, castor, and sesame oils),glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fattyacid esters of sorbitan, and mixtures thereof. Besides inert diluents,the oral compositions can also include adjuvants such as wetting agents,emulsifying and suspending agents, sweetening, flavoring, and perfumingagents.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions may be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectablesolution, suspension or emulsion in a nontoxic parenterally acceptablediluent or solvent, for example, as a solution in 1,3-butanediol. Amongthe acceptable vehicles and solvents that may be employed are water,Ringer's solution, U.S.P. and isotonic sodium chloride solution. Inaddition, sterile, fixed oils are conventionally employed as a solventor suspending medium. For this purpose any bland fixed oil can beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid are used in the preparation of injectables.

Injectable formulations can be sterilized, for example, by filtrationthrough a bacterial-retaining filter, or by incorporating sterilizingagents in the form of sterile solid compositions which can be dissolvedor dispersed in sterile water or other sterile injectable medium priorto use.

In order to prolong the effect of a provided compound, it is oftendesirable to slow the absorption of the compound from subcutaneous orintramuscular injection. This may be accomplished by the use of a liquidsuspension of crystalline or amorphous material with poor watersolubility. The rate of absorption of the compound then depends upon itsrate of dissolution that, in turn, may depend upon crystal size andcrystalline form. Alternatively, delayed absorption of a parenterallyadministered compound form is accomplished by dissolving or suspendingthe compound in an oil vehicle. Injectable depot forms are made byforming microencapsule matrices of the compound in biodegradablepolymers such as polylactide-polyglycolide. Depending upon the ratio ofcompound to polymer and the nature of the particular polymer employed,the rate of compound release can be controlled. Examples of otherbiodegradable polymers include poly(orthoesters) and poly(anhydrides).Depot injectable formulations are also prepared by entrapping thecompound in liposomes or microemulsions that are compatible with bodytissues.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activecompound is mixed with at least one inert, pharmaceutically acceptableexcipient or carrier such as sodium citrate or dicalcium phosphateand/or a) fillers or extenders such as starches, lactose, sucrose,glucose, mannitol, and silicic acid, b) binders such as, for example,carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone,sucrose, and acacia, c) humectants such as glycerol, d) disintegratingagents such as agar-agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates, and sodium carbonate, e) solutionretarding agents such as paraffin, f) absorption accelerators such asquaternary ammonium compounds, g) wetting agents such as, for example,cetyl alcohol and glycerol monostearate, h) absorbents such as kaolinand bentonite clay, and i) lubricants such as talc, calcium stearate,magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate,and mixtures thereof. In the case of capsules, tablets and pills, thedosage form may also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using such excipients as lactoseor milk sugar as well as high molecular weight polyethylene glycols andthe like. The solid dosage forms of tablets, dragees, capsules, pills,and granules can be prepared with coatings and shells such as entericcoatings and other coatings well known in the pharmaceutical formulatingart. They may optionally contain opacifying agents and can also be of acomposition that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner Examples of embedding compositions that can be usedinclude polymeric substances and waxes. Solid compositions of a similartype may also be employed as fillers in soft and hard-filled gelatincapsules using such excipients as lactose or milk sugar as well as highmolecular weight polyethylene glycols and the like.

Provided compounds can also be in micro-encapsulated form with one ormore excipients as noted above. The solid dosage forms of tablets,dragees, capsules, pills, and granules can be prepared with coatings andshells such as enteric coatings, release controlling coatings and othercoatings well known in the pharmaceutical formulating art. In such soliddosage forms the active compound may be admixed with at least one inertdiluent such as sucrose, lactose or starch. Such dosage forms may alsocomprise, as is normal practice, additional substances other than inertdiluents, e.g., tableting lubricants and other tableting aids such amagnesium stearate and microcrystalline cellulose. In the case ofcapsules, tablets and pills, the dosage forms may also comprisebuffering agents. They may optionally contain opacifying agents and canalso be of a composition that they release the active ingredient(s)only, or preferentially, in a certain part of the intestinal tract,optionally, in a delayed manner Examples of embedding compositions thatcan be used include polymeric substances and waxes.

Dosage forms for topical or transdermal administration of a compound ofthis invention include ointments, pastes, creams, lotions, gels,powders, solutions, sprays, inhalants or patches. The active componentis admixed under sterile conditions with a pharmaceutically acceptablecarrier and any needed preservatives or buffers as may be required.Ophthalmic formulation, ear drops, and eye drops are also contemplatedas being within the scope of this invention. Additionally, the presentinvention contemplates the use of transdermal patches, which have theadded advantage of providing controlled delivery of a compound to thebody. Such dosage forms can be made by dissolving or dispensing thecompound in the proper medium. Absorption enhancers can also be used toincrease the flux of the compound across the skin. The rate can becontrolled by either providing a rate controlling membrane or bydispersing the compound in a polymer matrix or gel.

Pharmaceutically acceptable compositions provided herein may beformulated for oral administration. Such formulations may beadministered with or without food. In some embodiments, pharmaceuticallyacceptable compositions of this disclosure are administered withoutfood. In other embodiments, pharmaceutically acceptable compositions ofthis disclosure are administered with food.

The amount of provided compounds that may be combined with carriermaterials to produce a composition in a single dosage form will varydepending upon the patient to be treated and the particular mode ofadministration.

It should also be understood that a specific dosage and treatmentregimen for any particular patient will depend upon a variety offactors, including age, body weight, general health, sex, diet, time ofadministration, rate of excretion, drug combination, the judgment of thetreating physician, and the severity of the particular disease beingtreated. The amount of a provided compound in the composition will alsodepend upon the particular compound in the composition.

Uses of Compounds and Pharmaceutically Acceptable Compositions

Compounds and compositions described herein are generally useful for theinhibition of ROR

. Thus, in some embodiments, the present invention provides a method oftreating inflammatory, metabolic and autoimmune diseases or disordersmediated by ROR

, comprising administering a provided compound or composition. Moreparticularly, the compounds and compositions described herein act asinverse agonists or antagonists of ROR

.

As used herein, the terms “treatment,” “treat,” and “treating” refer toreversing, alleviating, delaying the onset of, or inhibiting theprogress of a disease or disorder, or one or more symptoms thereof, asdescribed herein. In some embodiments, treatment may be administeredafter one or more symptoms have developed, i.e., therapeutic treatment.In other embodiments, treatment may be administered in the absence ofsymptoms. For example, treatment may be administered to a susceptibleindividual prior to the onset of symptoms (e.g., in light of a historyof symptoms and/or in light of genetic or other susceptibility factors),i.e., prophylactic treatment. Treatment may also be continued aftersymptoms have resolved, for example to prevent or delay theirrecurrence.

Diseases and conditions treatable according to the methods of theinvention include, but are not limited to, inflammatory, metabolic andautoimmune diseases or disorders mediated by ROR

. These diseases and conditions include, for example, asthma, chronicobstructive pulmonary disease (COPD), bronchitis, allergic rhinitis,atopic dermatitis, contact dermatitis, acne, urticaria, hives,angioedema, cystic fibrosis, allograft rejection, multiple sclerosis,Balo's concentric (circular) sclerosis, Balo disease, leukoencephalitisperiaxialis concentrica, encephalitis periaxialis concentrica,scleroderma, limited scleroderma, CREST syndrome, arthritis, rheumatoidarthritis, juvenile rheumatoid arthritis, reactive arthritis, Reiter'ssyndrome, osteoarthritis, ankylosing spondylitis, systemic lupuserythematosus (SLE), psoriasis, plaque psoriasis, guttate psoriasis,inverse psoriasis, pustular psoriasis, erythrodermic psoriasis,psoriatic epidermal hyperplasia, epidermal hyperplasia, Hashimoto'sdisease, pancreatitis, autoimmune diabetes, type I diabetes, autoimmuneocular disease, ulcerative colitis, Crohn's disease, regional enteritis,inflammatory bowel disease (IBD), inflammatory bowel syndrome (IBS),Sjögren's syndrome, optic neuritis, obesity, hepatosteatosis, adiposetissue-associated inflammation, insulin resistance, type II diabetes,neuromyelitis optica, myasthenia gravis, age related maculardegeneration, dry eye, uveitis, Guillain-Barré syndrome, psoriasis,psoriatic arthritis (PsA), steroid resistant asthma, Graves' disease,scleritis, endometriosis, obstructive sleep apnea syndrome (OSAS), Beh

et's disease, dermatomyositis, polymyositis, graft versus host disease,chronic graft versus host disease, acute graft versus host disease,primary biliary cirrhosis, liver fibrosis, non-alcoholic fatty liverdisease (NAFLD), sarcoidosis, primary sclerosing cholangitis, autoimmunethyroid disease, autoimmune polyendocrine syndrome type I, autoimmunepolyendocrine syndrome type II, celiac disease, celiac sprue,neuromyelitis, juvenile idiopathic arthritis, systemic sclerosis,myocardial infarction, pulmonary hypertension, osteoarthritis, cutaneousleishmaniasis, sinonasal polyposis, cancer, including but not limited tolung cancer, gastric cancer, breast cancer and colon cancer,thrombocytopenic purpura, idiopathic thrombocytopenic purpura (ITP),immune thrombocytopenic purpura, cartilage inflammation, bonedegradation, vasculitis, acute disseminated encephalomyelitis (ADEM),acute necrotizing hemorrhagic leukoencephalitis, Addison's disease,agammaglobulinemia, alopecia areata, amyloidosis, anti-glomerularbasement membrane (GBM) nephritis, anti-tubular basement membrane (TBM)nephritis, antiphospholipid syndrome (APS), autoimmune angioedema,autoimmune aplastic anemia, autoimmune dysautonomia, autoimmunehepatitis, autoimmune hyperlipidemia, autoimmune immunodeficiency,autoimmune inner ear disease (AIED), autoimmune myocarditis, autoimmuneoophoritis, autoimmune pancreatitis, autoimmune retinopathy, autoimmunethrombocytopenic purpura (ATP), autoimmune thyroid disease, autoimmuneurticaria, axonal and neuronal neuropathies, bullous pemphigoid,cardiomyopathy, Castleman disease, Chagas disease, chronic inflammatorydemyelinating polyneuropathy (CIDP), chronic recurrent multifocalostomyelitis (CRMO), Churg-Strauss syndrome, cicatricial pemphigoid,benign mucosal pemphigoid, Cogan's syndrome, cold agglutinin disease,congenital heart block, coxsackie myocarditis, essential mixedcryoglobulinemia, demyelinating neuropathies, dermatitis herpetiformis,Devic's disease, neuromyelitis optica, discoid lupus, Dressler'ssyndrome, eosinophilic esophagitis, eosinophilic fascitis, erythemanodosum, experimental allergic encephalomyelitis, Evans syndrome,fibrosing alveolitis, giant cell arteritis, temporal arteritis, giantcell myocarditis, glomerulonephritis, Goodpasture's syndrome,granulomatosis with polyangiitis (GPA), Wegener's granulomatosis,Hashimoto's encephalitis, Hashimoto's thyroiditis, hemolytic anemia,Henoch-Schonlein purpura, herpes gestationis, hypogammaglobulinemia, IgAnephropathy, IgG4-related sclerosing disease, immunoregulatorylipoproteins, inclusion body myositis, interstitial cystitis, juvenilemyositis, Kawasaki syndrome, Lambert-Eaton syndrome, leukocytoclasticvasculitis, lichen planus, lichen sclerosus, ligneous conjunctivitis,linear IgA disease (LAD), chronic Lyme disease, Meniere's disease,microscopic polyangiitis, mixed connective tissue disease (MCTD),Mooren's ulcer, Mucha-Habermann disease, myositis, narcolepsy,neuromyelitis optica, Devic's syndrome, neutropenia, ocular cicatricialpemphigoid, optic neuritis, palindromic rheumatism, pediatric autoimmuneneuropsychiatric disorders associated with streptococcus (PANDAS),paraneoplastic cerebellar degeneration, paroxysmal nocturnalhemoglobinuria (PNH), Parry-Romberg syndrome, Parsonnage-Turnersyndrome, pars planitis, peripheral uveitis, pemphigus, peripheralneuropathy, perivenous encephalomyelitis, pernicious anemia, POEMSsyndrome, polyarteritis nodosa, type I autoimmune polyglandularsyndrome, type II autoimmune polyglandular syndrome, type III autoimmunepolyglandular syndrome, polymyalgia rheumatic, postmyocardial infarctionsyndrome, postpericardiotomy syndrome, progesterone dermatitis, primarybiliary cirrhosis, primary sclerosing cholangitis, idiopathic pulmonaryfibrosis, pyoderma gangrenosum, pure red cell aplasia, Raynaud'sphenomenon, reflex sympathetic dystrophy, relapsing polychondritis,restless legs syndrome, retroperitoneal fibrosis, rheumatic fever,rheumatoid arthritis, sarcoidosis, Schmidt syndrome, sperm autoimmunity,stiff person syndrome, subacute bacterial endocarditis (SBE), Susac'ssyndrome, sympathetic ophthalmia, Takayasu's arteritis, temporalarteritis, giant cell arteritistesticular autoimmunity, Tolosa-Huntsyndrome, transverse myelitis, undifferentiated connective tissuedisease (UCTD), vesiculobullous dermatosis, and vitiligo.

Also included are diseases or disorders which are implicated by theregulation of the circadian rhythm of individuals and include, e.g.,major depression, seasonal affective disorder, post-traumatic stressdisorder (PTSD), bipolar disorder, autism, epilepsy, Alzheimer's andother central nervous system (CNS) disorders associated with alteredsleep and/or circadian rhythms.

In one embodiment, a human patient is treated with a compound of theinvention and a pharmaceutically acceptable carrier, adjuvant, orvehicle, wherein said compound is present in an amount to treat orameliorate one or more of the diseases and conditions recited above. Inanother embodiment, the diseases and conditions treated or amelioratedby a compound of the invention include, i.e., asthma, COPD, bronchitis,allergic rhinitis, atopic dermatitis, contact dermatitis, acne,urticaria, cystic fibrosis, allograft rejection, multiple sclerosis,scleroderma, arthritis, rheumatoid arthritis, juvenile rheumatoidarthritis, osteoarthritis, ankylosing spondylitis, SLE, psoriasis,Hashimoto's disease, pancreatitis, autoimmune diabetes, type I diabetes,autoimmune ocular disease, ulcerative colitis, Crohn's disease, regionalenteritis, IBD, IBS, Sjögren's syndrome, optic neuritis, obesity,hepatosteatosis, adipose tissue-associated inflammation, insulinresistance, type II diabetes, neuromyelitis optica, myasthenia gravis,age related macular degeneration, dry eye, uveitis, Guillain-Barrésyndrome, psoriasis, PsA, steroid resistant asthma, Graves' disease,scleritis, major depression, seasonal affective disorder, PTSD, bipolardisorder, autism, epilepsy, Alzheimer's, CNS disorders associated withaltered sleep and/or circadian rhythms, endometriosis, OSAS, Beh

et's disease, dermatomyositis, polymyocitis, graft versus host disease,primary biliary cirrhosis, liver fibrosis, NAFLD, sarcoidosis, primarysclerosing cholangitis, autoimmune thyroid disease, autoimmunepolyendocrine syndrome type I, autoimmune polyendocrine syndrome typeII, celiac disease, neuromyelitis, juvenile idiopathic arthritis,systemic sclerosis, myocardial infarction, pulmonary hypertension,osteoarthritis, cutaneous leishmaniasis, sinonasal polyposis, andcancer. In an alternative embodiment, the diseases and conditionstreated or ameliorated by a compound of the invention include, e.g.,asthma, atopic dermatitis, acne, Crohn's disease, regional enteritis,ulcerative colitis, Sjögren's syndrome, uveitis, Beh

et's disease, dermatomyositis, multiple sclerosis, ankylosingspondylitis, SLE, scleroderma, psoriasis, PsA, steroid resistant asthmaand rheumatoid arthritis in the patient.

The invention further relates to a combination therapy for treating orameliorating a disease or a disorder described herein. In someembodiments, the combination therapy comprises administering at leastone compound of the invention in combination with one or more agents fortreating or ameliorating inflammatory, metabolic and autoimmune diseasesor disorders mediated by ROR

. In some embodiments, the combination therapy comprises administeringat least one compound of the invention in combination with one or moreagents for treating or ameliorating a disease or a disorder describedherein. In some embodiments, the combination therapy comprisesadministering at least one compound of the invention in combination withone or more agents for the treatment of diseases including asthma,atopic dermatitis, acne, Crohn's disease, regional enteritis, ulcerativecolitis, Sjögren's syndrome, uveitis, Beh

et's disease, dermatomyositis, multiple sclerosis, ankylosingspondylitis, SLE, scleroderma, psoriasis, PsA, steroid resistant asthmaand rheumatoid arthritis.

The compounds according to the invention may also be used in combinationwith immunotherapies for the treatment of a disease or disorderdisclosed herein.

Combination therapy includes, e.g., co-administration of a compound ofthe invention and one or more other agents, sequential administration ofa compound of the invention and one or more other agents, administrationof a composition containing a compound of the invention and one or moreother agents, or simultaneous administration of separate compositionscontaining a compound of the invention and one or more other agents.

The invention further provides a method of treating a subject, such as ahuman, suffering from one of the abovementioned disorders or diseases.

The invention further relates to the use of provided compounds for theproduction of pharmaceutical compositions which are employed for thetreatment and/or prophylaxis and/or amelioration of the diseases anddisorders mentioned herein.

Compounds or compositions described herein may be administered using anyamount and any route of administration effective for treating orlessening the severity of one or more of the diseases and conditionsdescribed herein. The exact amount required will vary from subject tosubject, depending on the species, age, and general condition of thesubject, the severity of the infection, the particular agent, its modeof administration, and the like. Provided compounds are preferablyformulated in unit dosage form for ease of administration and uniformityof dosage. The expression “unit dosage form” as used herein refers to aphysically discrete unit of agent appropriate for the patient to betreated. It will be understood, however, that the total daily usage ofthe compounds and compositions of the present disclosure will be decidedby the attending physician within the scope of sound medical judgment.The specific effective dose level for any particular patient or organismwill depend upon a variety of factors including the disorder beingtreated and the severity of the disorder; the activity of the specificcompound employed; the specific composition employed; the age, bodyweight, general health, sex and diet of the patient; the time ofadministration, route of administration, and rate of excretion of thespecific compound employed; the duration of the treatment; drugs used incombination or coincidental with the specific compound employed, andlike factors well known in the medical arts.

Pharmaceutically acceptable compositions of this disclosure can beadministered to humans and other animals orally, rectally, parenterally,intracisternally, intravaginally, intraperitoneally, topically (as bypowders, ointments, or drops), bucally, as an oral or nasal spray, orthe like, depending on the severity of the infection being treated. Incertain embodiments, provided compounds may be administered orally orparenterally at dosage levels of about 0.01 mg/kg to about 50 mg/kg andpreferably from about 1 mg/kg to about 25 mg/kg, of subject body weightper day, one or more times a day, to obtain the desired therapeuticeffect.

The term “biological sample”, as used herein, includes, withoutlimitation, cell cultures or extracts thereof, biopsied materialobtained from a mammal or extracts thereof, and blood, saliva, urine,feces, semen, tears, or other body fluids or extracts thereof.

The amount of both, a provided compound and additional therapeutic agent(in those compositions which comprise an additional therapeutic agent asdescribed above) that may be combined with the carrier materials toproduce a single dosage form will vary depending upon the host treatedand the particular mode of administration.

In those compositions which comprise an additional therapeutic agent,that additional therapeutic agent and the provided compound may actsynergistically. Therefore, the amount of additional therapeutic agentin such compositions will be less than that required in a monotherapyutilizing only that therapeutic agent.

The amount of additional therapeutic agent present in the compositionsof this disclosure will be no more than the amount that would normallybe administered in a composition comprising that therapeutic agent asthe only active agent.

Exemplification

As depicted in the Examples below, in certain exemplary embodiments,compounds are prepared according to the following general procedures. Itwill be appreciated that, although the general methods depict thesynthesis of certain compounds of the present invention, the followinggeneral methods, and other methods known to one of ordinary skill in theart, can be applied to all compounds and subclasses and species of eachof these compounds, as described herein.

General Description of Synthesis

The compounds of the present invention can be readily prepared accordingto the following reaction schemes and examples, or modificationsthereof, using readily available starting materials, reagents andconventional synthesis procedures. Many of the reactions can also becarried out under microwave (MW) conditions or using conventionalheating or utilizing other technologies such as solid phasereagents/scavengers or flow chemistry. In these reactions, it is alsopossible to make use of variants which are themselves known to those ofordinary skill in the art, but are not mentioned in greater detail.Furthermore, other methods for preparing compounds of the invention willbe readily apparent to a person of ordinary skill in the art in light ofthe following reaction schemes and examples. In cases where syntheticintermediates and final products contain potentially reactive functionalgroups, for example amino, hydroxy, thiol and carboxylic acid groups,that may interfere with the desired reaction, it may be advantageous toemploy protected forms of the intermediate. Methods for the selection,introduction and subsequent removal of protecting groups are well knownto those skilled in the art. In the discussion below variables have themeanings indicated above unless otherwise indicated. The abbreviationsused in these experimental details are listed below and additional onesshould be known to a person skilled in the art of synthesis. Inaddition, one can refer to the following references for suitable methodsof synthesis as described in March, Advanced Organic Chemistry, 3rdedition, John Wiley & Sons, 1985, Greene and Wuts, Protective Groups inOrganic Synthesis, 2^(nd) edition, John Wiley & Sons, 1991, and RichardLarock, Comprehensive Organic Transformations, 4^(th) edition, VCHpublishers Inc., 1989.

Generally, reagents in the reaction schemes are used in equimolaramounts; however, in certain cases it may be desirable to use an excessof one reagent to drive a reaction to completion. This is especially thecase when the excess reagent can be readily removed by evaporation orextraction. Bases employed to neutralize HCl in reaction mixtures aregenerally used in slight to substantial excess (1.05-5 equivalents).

Where NMR data are presented, spectra were obtained on a Varian 400 (400MHz) or 300 (300 MHz) and are reported as ppm downfield fromtetramethylsilane with number of proton, multiplicities and couplingconstants indicated parenthetically along with reference to deuteratedsolvent.

The invention is illustrated by way of the following examples, in whichthe following abbreviations may be employed.

Abbreviation Meaning ACN, MeCN, acetonitrile CH₃CN AIBNazobisisobutyronitrile aq aqueous Boc tert-butoxycarbonyl ort-butoxycarbonyl brine saturated aqueous NaCl Cbz benzyloxy carbonyl Cpdcompound DCM or methylene chloride CH₂Cl₂ DIEA diisopropyl ethyl amineDMF dimethyl formamide DMS/Me₂S dimethyl sulfide DMSO dimethyl sulfoxideEDCI 1-(3-dimethylaminopropyl)-3-ethylcarbodiiimide hydrochloride EtIethyl iodide Et ethyl Et₂O ethyl ether Et₃SiH triethylsilane Et₃Ntriethylamine EtOAc , EA, ethyl acetate AcOEt EtOH ethanol h, hr hour(s)HATU O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium-hexafluorophosphate HBTUO-benzotriazole-1-yl-/N,N,N′,N′-tetramethyluronium- hexafluorophosphateHCl hydrochloric acid H₂O₂ hydrogen peroxide HPLC high performanceliquid chromatography i-BuOCOCl iso-butoxycarbonyl chloride ICliodochloride K₃PO₄ tripotassium phosphate LC-MS liquidchromatography-mass spectrometry LDA lithium diiisopropylamide MCPBA,meta-chloroperoxybenzoic acid m-CPBA MeOH methanol MeI methyl iodide Memethyl mg milligram min minute(s) mL milliliters mmol millimoles mp,m.p. melting point MS mass spectrometry MW, uwave microwave NBSN-bromosuccinimide n-BuLi n-butyllithium NMM N-methyl-morpholine NMPN-methyl-pyrrolidin-2-one OTf trifluoromethanesulfonate OTs tosylatePdCl₂dppf [1,1-bis(diphenylphosphino)ferrocene] dichloropalladium(ii)Pd₂(dba)₃ tris(dibenzylideneacetone)dipalladium(0) PE petroleum ether rtroom temperature sat. saturated SFC supercritical fluid chromatographyt-BuOK potassium tert butoxide t-BuLi tert butyl lithium t-BuOOH tertbutyl peroxide TBAF tetrabutylammonium fluoride TFA trifluoroacetic acidTHF tetrahydrofuran TLC thin layer chromatography Ti(OEt)₄ titaniumtetra ethoxide

Compounds according to Formula (I), can be prepared by reacting anintermediate compound of Formula (500) with an alkyl or benzyl halide,according to reaction Scheme 1, a reaction that is performed in a polaraprotic solvent, such as, for example, acetonitrile, in the presence ofa suitable base, such as, for example, N,N-diisopropylethylamine orpotassium carbonate. Alternatively, the final compounds according toFormula (I), can be prepared by reacting an intermediate compound ofFormula (500) with an aldehyde, according to reaction Scheme 1,following art-known reductive amination procedure, in the typicalsolvent, such as, for example, dichloroethane, dichloromethane, ormethanol; in the presence of suitable reducing reagent, such as sodiumcyanoborohydride or sodium triacetoxyborohydride. In reaction Scheme 1,all variables are defined as in Formula (I) and G¹ is a leaving group,such as for example, bromide, chloride, mesylate (methanesulfonate),tosylate (p-toluenesulfonate), trifluorormethanesulfonate (triflate), oriodide.

Intermediate compound of Formula (500) can be can be prepared bydeprotecting an intermediate compound of Formula (501), wherein Pg is asuitable nitrogen protecting group (Greene and Wuts, Protective Groupsin Organic Synthesis, 2^(nd) edition, John Wiley & Sons, 1991), e.g.,Pg=tert-butylcarbamate, removed with trifluoroacetic acid according toScheme 2. In reaction Scheme 2, all variables are defined as in Formula(I).

Intermediate compound of Formula (501) can be prepared from a carboxylicacid (502) and an amine (503), according to Scheme 3. The reaction isconveniently carried out in the presence of an activating reagent, forexample, N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride(EDCI) or O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU), in an organic solvent, for example,N,N-dimethylformamide or dichloromethane, optionally in the presence ofa base, e.g., N,N-diisopropylethylamine or triethylamine, at atemperature, for example in the range from 0 to 60° C.

Preparation of Intermediates Preparation A1: tert-butyl(S)-3-chloro-7-isopropyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylate

Step 1: ethyl (S)-4-((tert-butoxycarbonyl)amino)-5-methyl-3-oxohexanoate

To a stirred solution of Boc-Val-OH (3.11 g, 14.3 mmol) in THF (40 mL)at rt was added 1,1′-carbonyldiimidazole (3.48 g, 21.5 mmol). Themixture was stirred at rt for 1 h, then magnesium chloride (1.36 g, 14.3mmol) and ethyl potassium malonate (2.44 g, 14.3 mmol) were addedsuccessively. The mixture was then heated to 50° C. and stirred for 15h. The mixture was cooled to rt and quenched with 1 N HCl (100 mL). Theaqueous phase was extracted with EtOAc (3×100 mL), then the combinedorganic layer was washed with brine (50 mL). The organic layer was driedover anhydrous MgSO₄, filtered and concentrated under reduced pressure.The residue was purified by silica gel chromatography (eluting with 5%EtOAc in hexanes) to afford ethyl(S)-4-((tert-butoxycarbonyl)amino)-5-methyl-3-oxohexanoate (3.53 g, 86%yield) as a yellow oil. LC-MS t_(R)=0.91 min in 1 min chromatography, MS(ESI) m/z 288.3 [M+H]⁺. ¹H NMR (CDCl₃, 400 MHz): δ 5.08 (d, J=8.4 Hz,1H), 4.33 (dd, J=4.4 Hz, 8.8 Hz, 1H), 4.20 (q, J=7.2 Hz, 2H), 3.54 (s,2H), 2.27-2.17 (m, 1H), 1.44 (s, 9H), 1.27 (t, J=7.2 Hz, 3H), 1.01 (d,J=6.8 Hz, 3H), 0.82 (d, J=6.8 Hz, 3H).

Step 2:(S)-2-(1-((tert-butoxycarbonyl)amino)-2-methylpropyl)-5-chloronicotinate

To a mixture of ethyl(S)-4-((tert-butoxycarbonyl)amino)-5-methyl-3-oxohexanoate (9.68 g, 33.7mmol) from above in THF (100 mL) at 0° C. was added potassiumtert-butoxide (3.78 g, 35.4 mmol). The mixture was warmed to rt andstirred for 45 min, at which point 1,4-diazabicyclo[2.2.2]octane (3.78g, 33.7 mmol) and 2-chloro-1,3-bis(dimethylamino)trimethiniumhexaflurophosphate (15.5 g, 50.5 mmol) were added successively. Themixture was heated to 45° C. and stirred for 3 h, at which pointammonium acetate (5.19 g, 67.4 mmol) was added. The mixture was thenheated to reflux and stirred for 15 h. It was then cooled to rt andconcentrated under reduced pressure. The residue was dry-loaded onto asilica gel column and purified (eluting with 5% EtOAc in hexanes,gradient to 15%) to yield 6.09 g of ethyl(S)-2-(1-((tert-butoxycarbonyl)amino)-2-methylpropyl)-5-chloronicotinate(51%). LC-MS t_(R)=1.14 min in 1 min chromatography, MS (ESI) m/z 357.3[M+H]⁺. ¹H NMR (CDCl₃, 400 MHz): δ 8.61 (d, J=2.4 Hz, 1H), 8.18 (d,J=2.8 Hz, 1H), 5.71 (d, J=9.6 Hz, 1H), 5.62 (dd, J=5.2 Hz, 9.6 Hz, 1H),4.42 (q, J=7.2 Hz, 2H), 2.08-2.00 (m, 1H), 1.42 (s, 9H), 1.42 (t, J=7.2Hz, 3H), 0.93 (d, J=6.4 Hz, 3H), 0.83 (d, J=6.4 Hz, 3H).

Step 3: tert-butyl(S)-(1-(5-chloro-3-(hydroxymethyl)pyridin-2-yl)-2-methylpropyl)carbamate

To a stirred solution of ethyl(S)-2-(1-((tert-butoxycarbonyl)amino)-2-methylpropyl)-5-chloronicotinate(6.09 g, 17.1 mmol) at 0° C. in EtOH (70 mL) was added sodiumborohydride (1.30 g, 34.1 mmol). Calcium chloride (1.89 g, 17.1 mmol)was added portionwise while maintaining the temperature between 0° C.and 5° C. The resulting mixture was stirred at 0° C. for 90 min, thenquenched slowly at 0° C. with saturated aqueous ammonium chloridesolution (100 mL). The aqueous phase was extracted with EtOAc (3×100mL), then the combined organic layer was washed with brine (50 mL),dried over anhydrous MgSO₄, filtered and concentrated under reducedpressure. Crude tert-butyl(S)-(1-(5-chloro-3-(hydroxymethyl)pyridin-2-yl)-2-methylpropyl)carbamatewas carried forward without any purification. LC-MS t_(R)=0.94 min in 1min chromatography, MS (ESI) 315.3 [M+H]⁺. ¹H NMR (CDCl₃, 400 MHz): δ8.46 (d, J=2.4 Hz, 1H), 7.67 (d, J=2.8 Hz, 1H), 5.34 (d, J=9.2 Hz, 1H),4.99 (dd, J=2.0 Hz, 8.4 Hz, 1H), 4.54 (t, J=9.2 Hz, 1H), 4.41 (dd,J=10.0 Hz, 12.4 Hz, 1H), 4.33 (d, J=10.0 Hz, 1H), 2.18-2.12 (m, 1H),1.36 (s, 9H), 1.10 (d, J=6.4 Hz, 3H), 0.69 (d, J=6.8 Hz, 3H).

Step 4:(S)-(2-(1-((tert-butoxycarbonyl)amino)-2-methylpropyl)-5-chloropyridin-3-yl)methylmethanesulfonate

To a solution of tert-butyl(S)-(1-(5-chloro-3-(hydroxymethyl)pyridin-2-yl)-2-methylpropyl)carbamate(5.33 g, 16.9 mmol) in CH₂Cl₂ (70 mL) at 0° C. was added triethylamine(3.54 mL, 25.4 mmol) and methanesulfonyl chloride (1.44 mL, 18.6 mmol).The mixture was warmed to rt and stirred for 3 h, at which point it wasquenched with saturated aqueous sodium bicarbonate solution (100 mL).The aqueous phase was extracted with ethyl acetate (3×100 mL). Thecombined organic layer was washed with brine (50 mL), dried overanhydrous MgSO₄, filtered and concentrated under reduced pressure. Thecrude residue (a 3:1 mixture of(S)-(2-(1-((tert-butoxycarbonyl)amino)-2-methylpropyl)-5-chloropyridin-3-yl)methylmethanesulfonate and tert-butyl(S)-(1-(5-chloro-3-(chloromethyl)pyridin-2-yl)-2-methylpropyl)carbamate)was carried forward without any purification. LC-MS t_(R)=1.01 min in 1min chromatography, MS (ESI) m/z 393.3 [M+H]⁺. ¹H NMR (CDCl₃, 400 MHz):δ 8.53 (d, J=2.4 Hz, 1H), 7.74 (d, J=2.8 Hz, 1H), 5.44 (d, J=12.4 Hz,1H), 5.37 (d, J=12.8 Hz, 1H), 5.31 (d, J=8.4 Hz, 1H), 4.59 (t, J=9.2 Hz,1H), 3.13 (s, 3H), 2.13-2.04 (m, 1H), 1.36 (s, 9H), 1.03 (d, J=6.8 Hz,3H), 0.77 (d, J=6.8 Hz, 3H). Characterization data from a purifiedsample of(S)-(2-(1-((tert-butoxycarbonyl)amino)-2-methylpropyl)-5-chloropyridin-3-yl)methylmethanesulfonate.

Step 5: tert-butyl(S)-3-chloro-7-isopropyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylate

To a solution of(S)-(2-(1-((tert-butoxycarbonyl)amino)-2-methylpropyl)-5-chloropyridin-3-yl)methylmethanesulfonate and tert-butyl(S)-(1-(5-chloro-3-(chloromethyl)pyridin-2-yl)-2-methylpropyl)carbamate(3:1 mixture, 6.39 g, 16.9 mmol) in THF (75 mL) at 0° C. was addedsodium hydride (60% dispersion in mineral oil, 811 mg, 20.3 mmol). Themixture was warmed to rt and stirred for 15 h, at which point it wasquenched with saturated aqueous ammonium chloride solution (100 mL). Theaqueous phase was extracted with ethyl acetate (3×100 mL). The combinedorganic layer was washed with brine (50 mL), dried over anhydrous MgSO₄,filtered and concentrated under reduced pressure. The residue waspurified by silica gel chromatography (eluting with 5% EtOAc in hexanes,gradient to 10%) to give tert-butyl(S)-3-chloro-7-isopropyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylate(4.31 g, 85% yield over 3 steps) as a yellow oil. LC-MS t_(R)=1.12 minin 1 min chromatography, MS (ESI) m/z 297.3 [M+H]⁺. ¹H NMR (CDCl₃, 400MHz, mixture of rotamers): δ 8.43 (s, 1H), 7.56 (s, 0.6H), 7.50 (s,0.4H), 4.96 (s, 0.4H), 4.87 (s, 0.6H), 4.86 (d, J=16.0 Hz, 0.6H), 4.74(d, J=15.6 Hz, 0.4H), 4.52 (d, J=12.0 Hz, 0.4H), 4.49 (d, J=15.2 Hz,0.6H), 2.60-2.51 (m, 0.4H), 2.40-2.36 (m, 0.6H), 1.49 (s, 9H), 1.08 (d,J=7.2 Hz, 1.2H), 0.99 (d, J=7.2 Hz, 1.8H), 0.78 (d, J=6.8 Hz, 1.8H),0.72 (d, J=6.8 Hz, 1.2H).

Step 6: tert-butyl(S)-3-chloro-7-isopropyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylate

Potassium carbonate (758 mg, 5.49 mmol) and 4 Å molecular sieves (250mg) were placed in a 50 mL round-bottom flask which was then flamedried. Palladium (II) acetate (32.8 mg, 146 μmol) and1,3-bis(dicyclohexylphosphonium)propane bis (tetrafluoroborate) (179 mg,292 μmol) were added to the flask, which was then sealed with a septum.Tert-butyl(S)-3-chloro-7-isopropyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylate(1.09 g, 3.66 mmol) was dissolved in DMF (12 mL) and added to the flask,followed by 1-butanol (3.34 mL, 36.6 mmol). The flask was then evacuatedand backfilled with CO three times, with the final time under a balloonof 1 atm of CO. The flask was heated to 100° C. and stirred for 6 h. Themixture was then cooled to rt and quenched with 1 N NaOH (25 mL). Themixture was stirred for 30 min, at which point isopropyl acetate (50 mL)was added. The phases were separated, then the organic phase wasextracted with 1 N NaOH (2×50 mL), then the combined aqueous layer wasacidified to pH=2 with concentrated HCl. The aqueous layer was thenextracted with EtOAc (3×25 mL), then the combined organic layer wasdried over anhydrous MgSO₄, filtered and concentrated under reducedpressure. The crude residue(S)-6-(tert-butoxycarbonyl)-7-isopropyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-3-carboxylicacid was carried forward without any purification.

Preparation A2:(S)-6-(tert-butoxycarbonyl)-7-ethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-3-carboxylicacid

Step 1: (S)-methyl 4-((tert-butoxycarbonyl)amino)-3-oxohexanoate

To a mixture of (S)-2-((tert-butoxycarbonyl)amino)butanoic acid (200 g,0.985 mol) in THF (1 L) was added 1,1′-carbonyldiimidazole (176 g, 1.084mol) at rt. The mixture was stirred at rt for 1 h. Then magnesiumchloride (101 g, 1.084 mol) and potassium 3-methoxy-3-oxopropanoate (169g, 1.084 mol) were added. After addition, the mixture was stirred at 50°C. for 3 h. TLC (petroleum ether:ethyl acetate=5:1) showed the startingmaterial was consumed. The mixture was cooled and filtered; the filtercake was washed with THF (300 mL) and filtered. The combined filtratewas concentrated under reduced pressure and the residue was diluted withEtOAc (1 L) washed with water (800 mL), brine (800 mL), dried overanhydrous sodium sulfate, filtered and concentrated under reducedpressure to give (S)-methyl4-((tert-butoxycarbonyl)amino)-3-oxohexanoate (117 g, 45%) as a yellowoil, which was used in the next step directly without furtherpurification.

Step 2: (S)-methyl2-(1-((tert-butoxycarbonyl)amino)propyl)-5-chloronicotinate

To a solution of (S)-methyl4-((tert-butoxycarbonyl)amino)-3-oxohexanoate (117 g, 0.452 mol) inanhydrous THF (1.0 L) was added potassium tert-butoxide (51.3 g, 0.474mol) in portions at 0° C. After stirring for 1 h at 0° C.,1,4-diazabicyclo[2.2.2]octane (53.1 g, 0.474 mol) and2-chloro-1,3-bis(dimethylamino)trimethinium hexafluorophosphate (145 g,0.474 mol) were added portionwise to the mixture at 0° C. The mixturewas stirred at rt for 3 h and the solution turned red. Ammonium acetate(104 g, 1.355 mol) was added to the solution, and the resulting mixturewas stirred at rt overnight. TLC (petroleum ether:ethyl acetate=5:1)showed no starting material remaining. The mixture was cooled andfiltered; the filtrate was concentrated under reduced pressure and theresidue was diluted with EtOAc (1.5 L) and washed with water (1 L),brine (1 L), dried over anhydrous sodium sulfate, filtered andconcentrated under reduced pressure. The residue was purified by silicagel chromatography, eluting with petroleum ether:ethyl acetate=25:1-17:1to give (S)-methyl2-(1-((tert-butoxycarbonyl)amino)propyl)-5-chloronicotinate (53 g, 36%)as a yellow oil. LC-MS t_(R)=0.961 min in 5-95AB_1.5 min chromatography(Merck RP-18e 25-2 mm), MS (ESI) m/z 272.9 [M−55]⁺. ¹H NMR (CDCl₃, 400MHz): δ 8.61 (d, J=2.4 Hz, 1H), 8.18 (d, J=2.4 Hz, 1H), 5.71-5.54 (m,1H), 3.94 (s, 3H), 1.86-1.83 (m, 1H), 1.60-1.58 (m, 1H), 1.26 (s, 9H),0.95 (t, J=7.2 Hz, 3H).

Step 3: (S)-tert-butyl(1-(5-chloro-3-(hydroxymethyl)pyridin-2-yl)propyl)carbamate

To a solution of (S)-methyl2-(1-((tert-butoxycarbonyl)amino)propyl)-5-chloronicotinate (60 g, 0.183mol) in anhydrous ethanol (800 mL) was added sodium borohydrideportionwise (14.0 g, 0.366 mol) at 0° C. slowly and stirred for about 20min To the resulting mixture was added calcium chloride (20.1 g, 0.183mol) at 0° C. slowly in four portions. The mixture was stirred at 0° C.for 1.5 h. TLC (petroleum ether:ethyl acetate=5:1) showed no startingmaterial remaining. The mixture was quenched with saturated aqueousNH₄Cl solution (50 mL) at 0° C. slowly and then stirred for 30 min. Themixture was concentrated to remove part of the ethanol, then extractedwith ethyl acetate (3×1.0 L). The combined organic layers were washedwith water (2×1.0 L) and saturated aqueous NaHCO₃ solution (500 mL),dried over anhydrous sodium sulfate, filtered and concentrated underreduced pressure to give (S)-tert-butyl(1-(5-chloro-3-(hydroxymethyl)pyridin-2-yl)propyl)carbamate (50 g, 91%)as a yellow solid, which was used directly for the next step withoutfurther purification. LC-MS t_(R)=0.703 min in 5-95AB_1.5 minchromatography (Merck RP-18e 25-2 mm), MS (ESI) m/z 244.9 [M−55]⁺.

Step 4: (S)-tert-butyl(1-(5-chloro-3-(chloromethyl)pyridin-2-yl)propyl)carbamate &(S)-(2-(1-((tert-butoxycarbonyl)amino)propyl)-5-chloropyridin-3-yl)methyl4-methylbenzenesulfonate

To a solution of (S)-tert-butyl(1-(5-chloro-3-(hydroxymethyl)pyridin-2-yl)propyl)carbamate (50 g, 0.167mol) in CH₂Cl₂ (500 mL) was added triethylamine (50.5 g, 0.499 mol) andp-toluenesulfonyl chloride (63 g, 0.333 mol) at 0° C. The mixture wasstirred at rt for 1.5 h. TLC (petroleum ether:ethyl acetate=5:1) showedno starting material remaining. The mixture was diluted with CH₂Cl₂ (500mL), washed with water (2×1.0 L) and brine (1 L), dried over anhydrousNa₂SO₄, filtered and concentrated under reduced pressure. The residuewas purified by silica gel chromatography (eluting with petroleumether:ethyl acetate=0 to 10:1) to give (S)-tert-butyl(1-(5-chloro-3-(chloromethyl)pyridin-2-yl)propyl)carbamate (11 g, 21%)as a red solid and(S)-(2-(1-((tert-butoxycarbonyl)amino)propyl)-5-chloropyridin-3-yl)methyl4-methylbenzenesulfonate (23 g, 30%) as a yellow solid. LC-MSt_(R)=0.840 min in 5-95AB_1.5 min chromatography (Merck RP-18e 25-2 mm),MS (ESI) m/z 262.9 [M−55]⁺.

Step 5: (S)-tert-butyl3-chloro-7-ethyl-5H-pyrrolo[3,4-b]pyridine-6(7H)-carboxylate

Procedure same as that for tert-butyl(S)-3-chloro-7-isopropyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylatewith (S)-tert-butyl (1-(5-chloro-3-(chloromethyl)pyridin-2-yl)propyl)carbamate (11 g, 34.6 mmol) and(S)-(2-(1-((tert-butoxycarbonyl)amino)propyl)-5-chloropyridin-3-yl)methyl4-methylbenzenesulfonate as the starting materials. ¹H NMR (CDCl₃, 400MHz): δ 8.45 (s, 1H), 7.56 (s, 0.6H), 7.50 (s, 0.4H), 5.30 (s, 0.4H),4.94 (s, 0.6H), 4.77 (d, J=15.6 Hz, 0.6H), 4.70 (d, J=15.6 Hz, 0.4H),4.55 (s, 0.6H), 4.51 (s, 0.4H), 2.26-2.14 (m, 1H), 2.04-1.96 (m, 1H),1.51 (s, 9H), 0.67 (t, J=7.6 Hz, 3H).

Step 6:(S)-6-(tert-butoxycarbonyl)-7-ethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-3-carboxylicacid

Potassium carbonate (33.8 g, 24.5 mmol) and 4 Å molecular sieves (11.30g) were placed in a 50 mL round-bottom flask which was then flame dried.Palladium (II) acetate (757 mg, 3.26 mmol) and1,3-bis(dicyclohexylphosphonium)propane bis(tetrafluoroborate) (3.98 g,6.52 mmol) were added to the flask, which was then sealed with a septum.(S)-tert-butyl3-chloro-7-ethyl-5H-pyrrolo[3,4-b]pyridine-6(7H)-carboxylate (23 g, 81.5mmol) was dissolved in DMF (250 mL) and added to the flask, followed by1-butanol (60.4 g, 815 mmol). The flask was then evacuated andbackfilled with CO four times. CO gas (from a gas bag, a volume of 30 L)was then bubbled into the flask, with heating to 100° C. overnight. LCMSshowed no starting material remaining. The reaction was then cooled tort and 6 g of NaOH in 100 ml water was added. After stirring for 1 h,LCMS showed a 100% conversion to the acid product. The mixture wasacidified to pH=3-4 with 1 N HCl solution and extracted with ethylacetate (3×1 L). The combined organic layers were washed with water (2×1L) and brine (1 L), dried over anhydrous sodium sulfate, filtered andconcentrated under reduced pressure. The residue was purified by silicagel chromatography (eluting with petroleum ether:ethyl acetate=20:1-1:1)to give the desired product (20 g, 84%, ee=28.24%), which was thenpurified by SFC separation to give(S)-6-(tert-butoxycarbonyl)-7-ethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-3-carboxylicacid (9 g, ee=95.49%) as a yellow solid. LC-MS t_(R)=0.813 min in5-95AB_1.5 min chromatography (Merck RP-18e 25-2 mm), MS (ESI) m/z 292.9[M+H]⁺. ¹H NMR (CDCl₃, 400 MHz): δ 9.23 (s, 1H), 7.28 (s, 0.6H), 8.23(s, 0.4H), 5.21 (s, 0.4H), 5.11 (s, 0.6H), 4.89 (d, J=16.0 Hz, 0.6H),4.80 (d, J=15.6 Hz, 0.4H), 4.65 (s, 0.6H), 4.61 (s, 0.4H), 2.25-2.14 (m,1H), 2.08-2.04 (m, 1H), 1.53 (s, 9H), 0.68 (t, J=7.6 Hz, 3H). Isomer SFC1215-186-P1A_1 t_(R)=6.71 in 15 min chromatography (Column: AD-H, MethodName: 5-40_2.5 ml.met, ee=95.49%).

Preparation A3:(S)-6-(tert-butoxycarbonyl)-7-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-3-carboxylicacid

Step 1:(R,E)-2-methyl-N-((tetrahydro-2H-pyran-4-yl)methylene)propane-2-sulfinamide

Procedure same as that for(R,E)-N-(2-((tert-butyldimethylsilyl)oxy)ethylidene)-2-methylpropane-2-sulfinamidewith tetrahydro-2H-pyran-4-carbaldehyde and(R)-2-methylpropane-2-sulfinamide as the starting martials. LC-MSt_(R)=1.072 min in 5-95AB_1.5 min chromatography (Merck RP-18e 25-2 mm),MS (ESI) m/z 217.9 [M+H]⁺.

Step 2: 2,5-dibromo-3-(bromomethyl)pyridine

A mixture of 2,5-dibromo-3-methylpyridine (20.0 g, 80.0 mmol),N-bromosuccinimide (12.8 g, 72 mmol) and benzoyl peroxide (1.03 g, 4mmol) in CCl₄ (300 mL) was heated to reflux for 3 h. The mixture wascooled to rt, washed with water (2×100 mL) and brine (100 mL), driedover anhydrous sodium sulfate, filtered and concentrated under vacuum.The residue was purified by preparative HPLC (HCl) to give2,5-dibromo-3-(bromomethyl)pyridine (11.0 g, 42%) as a white solid. ¹HNMR: (CDCl₃, 400 MHz): δ 8.38-8.39 (d, J=2.4 Hz, 1H), 7.91-7.92 (d,J=2.4 Hz, 1H), 4.51 (s, 2H).

Step 3: 2,5-dibromo-3-(methoxymethyl)pyridine

A mixture of 2,5-dibromo-3-(bromomethyl)pyridine (11.0 g, 33.3 mmol) andsodium methoxide (5.4 g, 100 mmol) in methanol (150 mL) was stirred atrt for 18 h. The mixture was filtered and the filtrate was concentratedunder vacuum. The residue was purified by silica gel chromatography(eluting with petroleum ether:ethyl acetate=10:1) to give2,5-dibromo-3-(methoxymethyl)pyridine (8.7 g, 93%) as a liquid. ¹H NMR(CDCl₃, 400 MHz): δ 8.35 (s, 1H), 7.93 (s, 1H), 4.45 (s, 2H), 3.53 (s,3H).

Step 4:(R)—N—((S)-(5-bromo-3-(methoxymethyl)pyridin-2-yl)(tetrahydro-2H-pyran-4-yl)methyl)-2-methylpropane-2-sulfinamide&(R)—N—((R)-(5-bromo-3-(methoxymethyl)pyridin-2-yl)(tetrahydro-2H-pyran-4-yl)methyl)-2-methylpropane-2-sulfinamide

Procedure same as that for(R)—N—((R)-2-((tert-butyldimethylsilyl)oxy)-1-(4-(ethylthio)phenyl)ethyl)-2-methylpropane-2-sulfinamidewith 2,5-dibromo-3-(methoxymethyl)pyridine and (R)-tert-butylsulfonamideas the starting materials. LC-MS t_(R)=0.824 min in 5-95AB_1.5 minchromatography (Merck RP-18e 25-2 mm), MS (ESI) 420.9 [M+1]⁺. Isomer SFCt_(R)=11.19 and 11.71 in 25 min chromatography (Column: AS-RH_10-80_B_08ML_25 MIN), ee=97.16%.

Step 5:(S)-(2-(amino(tetrahydro-2H-pyran-4-yl)methyl)-5-bromopyridin-3-yl)methanol

To a solution of (R)—N—((S)-(5-bromo-3-(methoxymethyl)pyridin-2-yl)(tetrahydro-2H-pyran-4-yl)methyl)-2-methylpropane-2-sulfinamide (1.5 g,3.6 mmol) in CH₂Cl₂ (30 mL) was added boron tribromide (4.5 g, 18.0mmol) at −30° C. The mixture was stirred at −30° C. for 2 h. MeOH (5 mL)was then carefully added to the mixture at −30° C. and the reaction wasallowed to warm to rt. Upon reaching rt, the mixture was concentratedunder reduced pressure to afford crude(S)-(2-(amino(tetrahydro-2H-pyran-4-yl)methyl)-5-bromopyridin-3-yl)methanol(1.0 g, crude) as an oil, which was used for the next step withoutfurther purification. LC-MS t_(R)=0.176 min in 0-30 CD_POS.M (MerckRP-18e 25-2 mm), MS (ESI) m/z 303.0 [M+1]⁺.

Step 6: (S)-tert-butyl((5-bromo-3-(hydroxymethyl)pyridin-2-yl)(tetrahydro-2H-pyran-4-yl)methyl)carbamate

A mixture of(S)-(2-(amino(tetrahydro-2H-pyran-4-yl)methyl)-5-bromopyridin-3-yl)methanol(1.0 g, 3.3 mmol), di-tert-butyl dicarbonate (1.1 g, 5.0 mmol) andtriethylamine (1.0 g, 10 mmol) in CH₂Cl₂ (10 mL) was stirred at rt for16 h. The mixture was quenched with water (10 mL) and extracted withCH₂Cl₂ (3×10 mL). The combined organic layer was washed with brine (2×10mL), dried over anhydrous Na₂SO₄, filtered and concentrated underreduced pressure. The residue was purified by silica gel chromatography(eluting with petroleum ether:ethyl acetate=5:1-3:1) to give(S)-tert-butyl((5-bromo-3-(hydroxymethyl)pyridin-2-yl)(tetrahydro-2H-pyran-4-yl)methyl)carbamate(500 mg, 38%) as an oil. LC-MS t_(R)=2.870 min in 0-30CD_POS.Mchromatography (Merck RP-18e 25-2 mm), MS (ESI) m/z 401.1 [M+1]⁺.

Step 7: (S)-tert-butyl((5-bromo-3-(chloromethyl)pyridin-2-yl)(tetrahydro-2H-pyran-4-yl)methyl)carbamate

Procedure same as that for(S)-(2-(1-((tert-butoxycarbonyl)amino)-2-methylpropyl)-5-chloropyridin-3-yl)methylmethanesulfonate with (S)-tert-butyl((5-bromo-3-(hydroxymethyl)pyridin-2-yl)(tetrahydro-2H-pyran-4-yl)methyl)carbamateas the starting material. LC-MS t_(R)=0.943 min in 5-95AB_1.5 minchromatography (Merck RP-18e 25-2 mm), MS (ESI) m/z 365.0 [M+1]⁺.

Step 8: (S)-tert-butyl3-bromo-7-(tetrahydro-2H-pyran-4-yl)-5H-pyrrolo[3,4-b]pyridine-6(7H)-carboxylate

Procedure same as that for tert-butyl(S)-3-chloro-7-isopropyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylatewith (S)-tert-butyl ((5-bromo-3-(chloromethyl)pyridin-2-yl)(tetrahydro-2H-pyran-4-yl)methyl)carbamate (350 mg, 0.83 mmol) as thestarting material. LC-MS t_(R)=1.723 min in 5-95AB_1.5 minchromatography (Merck RP-18e 25-2 mm), MS (ESI) m/z 385.1 [M+1]⁺. IsomerSFC t_(R)=2.930 and 4.433 in 12 min chromatography (Column:AD_3_B2_5_40_25 ML), ee=97.80%.

Step 9:(S)-6-(tert-butoxycarbonyl)-7-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-3-carboxylicacid

Procedure same as that for(S)-6-(tert-butoxycarbonyl)-7-isopropyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-3-carboxylicacid with (S)-tert-butyl3-bromo-7-(tetrahydro-2H-pyran-4-yl)-5H-pyrrolo[3,4-b]pyridine-6(7H)-carboxylateas the starting material. LC-MS t_(R)=0.685 min in 5-95AB_1.5 minchromatography (Merck RP-18e 25-2 mm), MS (ESI) 349.1 [M+1]⁺. Isomer SFCt_(R)=5.146 and 5.602 in 15 min chromatography (Column: AD-H_5_5_40_2.35ML), ee=95.89%.

Preparation A4:(S)-6-(tert-butoxycarbonyl)-7-((tetrahydro-2H-pyran-4-yl)methyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-3-carboxylicacid

Step 1: ethyl 2-(dihydro-2H-pyran-4(3H)-ylidene)acetate

To a mixture of dihydro-2H-pyran-4(3H)-one (22.5 g, 225 mmol) inacetonitrile (500 mL) was added(carbethoxymethylene)triphenylphosphorane (86.1 g, 247 mmol) at 0° C.The mixture was stirred at 85-90° C. (oil bath) for 48 h. LCMS showed astrong product peak and most of(carbethoxymethylene)triphenylphosphorane consumed. The mixture wascooled to rt, filtered and concentrated under reduced pressure. Theresidue was purified by silica gel chromatography (eluting withpetroleum ether:ethyl acetate=10:1) to give ethyl2-(dihydro-2H-pyran-4(3H)-ylidene)acetate (38 g, 99%) as a yellow solid.¹H NMR (CDCl₃, 400 MHz): δ 5.66 (s, 1H), 4.09-4.14 (q, J=7.2 Hz, 2H),3.71-3.77 (m, 4H), 2.98-3.01 (t, J=5.2 Hz, 2H), 2.30-2.32 (t, J=4.8 Hz,2H), 1.24-1.28 (t, J=7.2 Hz, 3H).

Step 2: ethyl 2-(tetrahydro-2H-pyran-4-yl)acetate

A mixture of ethyl 2-(dihydro-2H-pyran-4(3H)-ylidene)acetate (21 g, 123mmol) and dry Pd/C (2.5 g) in methanol (300 mL) was stirred at 16-19° C.for 18 h under H₂ (30 psi). TLC (petroleum ether:ethyl acetate=3:1)showed no starting material remaining. The mixture was filtered and thefiltrate was concentrated under reduced pressure to give crude ethyl2-(tetrahydro-2H-pyran-4-yl)acetate (20 g, 94%) as an oil, which wasused for the next step directly without further purification. ¹H NMR(CDCl₃, 400 MHz): δ 4.11-4.15 (q, J=7.2 Hz, 2H), 3.93-3.95 (d, J=10.8Hz, 2H), 3.37-3.43 (t, J=11.6 Hz, 2H), 2.23-2.25 (d, J=6.8 Hz, 2H),1.99-2.03 (m, 1H), 1.62-1.65 (m, 2H), 1.32-1.36 (m, 2H), 1.24-1.27 (t,J=7.2 Hz, 3H).

Step 3: 2-(tetrahydro-2H-pyran-4-yl)ethanol

To a mixture of ethyl 2-(tetrahydro-2H-pyran-4-yl)acetate (20 g, 116mmol) in anhydrous THF (300 mL) was added lithium aluminum hydride (8.8g, 232 mmol) portionwise at 0° C. The mixture was stirred at 11-13° C.for 18 h. TLC (petroleum ether: ethyl acetate=3:1) showed no startingmaterial remaining. The mixture was quenched with water (9 mL), 10% aq.NaOH solution (9 mL) and water (18 mL) successively at 0° C., filteredand concentrated under reduced pressure to give crude2-(tetrahydro-2H-pyran-4-yl)ethanol (11.7 g, 77%) as an oil, which wasused for the next step directly without further purification. ¹H NMR(CDCl₃, 400 MHz): δ 3.86-3.90 (m, 2H), 3.58-3.61 (t, J=6.4 Hz, 2H),3.32-3.35 (t, J=11.6 Hz, 2H), 2.69-2.70 (m, 1H), 1.61-1.63 (m, 3H),1.54-1.60 (m, 2H), 1.43-1.45 (m, 2H).

Step 4: 2-(tetrahydro-2H-pyran-4-yl)acetaldehyde

A mixture of 2-(tetrahydro-2H-pyran-4-yl)ethanol (11.70 g, 89.9 mmol)and pyridinium chlorochromate (38.8 g, 179.8 mmol) in CH₂Cl₂ (200 mL)was stirred at 16-19° C. for 17 h. TLC (petroleum ether:ethylacetate=3:1) showed the reaction was complete. The mixture was filteredwith Kieselguhr and the filtrate (150 mL) was used for the next stepdirectly without further purification.

Step 5:(R,E)-2-methyl-N-(2-(tetrahydro-2H-pyran-4-yl)ethylidene)propane-2-sulfinamide

Procedure same as that for(R,E)-N-(2-((tert-butyldimethylsilyl)oxy)ethylidene)-2-methylpropane-2-sulfinamidewith 2-(tetrahydro-2H-pyran-4-yl)acetaldehyde and(R)-2-methylpropane-2-sulfinamide (21.8 g, 179.8 mmol) as the startingmaterials. LC-MS t_(R)=1.082 min in 10-80AB_2.0 min chromatography(Xtimate 3 um, C18, 2.1*30 mm), MS (ESI) m/z 232.0 [M+H]⁺. ¹H NMR(CDCl₃, 400 MHz): δ 8.06-8.09 (t, J=5.2 Hz, 1H), 3.38-3.44 (m, 4H),2.47-2.50 (m, 2H), 2.29-2.31 (m, 1H), 1.62-1.68 (m, 4H).

Step 6:(R)—N—((S)-1-(5-bromo-3-(methoxymethyl)pyridin-2-yl)-2-(tetrahydro-2H-pyran-4-yl)ethyl)-2-methylpropane-2-sulfinamideand(R)—N—((R)-1-(5-bromo-3-(methoxymethyl)pyridin-2-yl)-2-(tetrahydro-2H-pyran-4-yl)ethyl)-2-methylpropane-2-sulfinamide

Procedure same as that for(R)—N—((R)-2-((tert-butyldimethylsilyl)oxy)-1-(4-(ethylthio)phenyl)ethyl)-2-methylpropane-2-sulfinamidewith 2,5-dibromo-3-(methoxymethyl)pyridine and(R,E)-2-methyl-N-(2-(tetrahydro-2H-pyran-4-yl)ethylidene)propane-2-sulfinamideas the starting materials. LC-MS t_(R)=0.849 min in 5-95AB_1.5 minchromatography (Merck RP-18e 25-2 mm), MS (ESI) m/z 433.0 [M+H]⁺. IsomerSFC t_(R)=12.39 in 25 min chromatography (Column: AD-RH_10-80_B_08 ML_25min), ee=97.16%. Another Isomer: LC-MS t_(R)=1.081 min in 10-80AB_2.0min chromatography (Xtimate, 2.1*30 mm, 3 um), MS (ESI) m/z 433.0[M+H]⁺. Isomer SFC t_(R)=13.04 and 15.09 in 25 min chromatography(Column: AD-RH_10-80_B_08 ML_25 min), ee=96.46%.

Step 7:(S)-(2-(1-amino-2-(tetrahydro-2H-pyran-4-yl)ethyl)-5-bromopyridin-3-yl)methanol

Procedure same as that for(S)-(2-(amino(tetrahydro-2H-pyran-4-yl)methyl)-5-bromopyridin-3-yl)methanolwith(R)—N—((S)-1-(5-bromo-3-(methoxymethyl)pyridin-2-yl)-2-(tetrahydro-2H-pyran-4-yl)ethyl)-2-methylpropane-2-sulfinamideas the starting material. LC-MS t_(R)=0.307 min in 0-30AB_2.0 minchromatography (Xtimate, 2.1*30 mm, 3 um), MS (ESI) m/z 315.0 [M+H]⁺.

Step 8: (S)-tert-butyl1-(5-bromo-3-(hydroxymethyl)pyridin-2-yl)-2-(tetrahydro-2H-pyran-4-yl)ethylcarbamate

Procedure same as that for (S)-tert-butyl((5-bromo-3-(hydroxymethyl)pyridin-2-yl)(tetrahydro-2H-pyran-4-yl)methyl)carbamatewith(S)-(2-(1-amino-2-(tetrahydro-2H-pyran-4-yl)ethyl)-5-bromopyridin-3-yl)methanolas the starting material. LC-MS t_(R)=0.716 min in 5-95AB_1.5 minchromatography (MK RP-18e 25-2 mm), MS (ESI) m/z 414.9 [M+H]⁺.

Step 9: (S)-tert-butyl1-(5-bromo-3-(chloromethyl)pyridin-2-yl)-2-(tetrahydro-2H-pyran-4-yl)ethylcarbamate

Procedure same as that for(S)-(2-(1-((tert-butoxycarbonyl)amino)-2-methylpropyl)-5-chloropyridin-3-yl)methylmethanesulfonate with (S)-tert-butyl1-(5-bromo-3-(hydroxymethyl)pyridin-2-yl)-2-(tetrahydro-2H-pyran-4-yl)ethylcarbamateas the starting material. LC-MS t_(R)=0.962 min in 5-95AB_1.5 minchromatography (Merck RP-18e 25-2 mm), MS (ESI) m/z 434.9 [M+1]⁺.

Step 10: (S)-tert-butyl3-bromo-7-((tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrrolo[3,4-b]pyridine-6(7H)-carboxylate

Procedure same as that for tert-butyl(S)-3-chloro-7-isopropyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylatewith (S)-tert-butyl1-(5-bromo-3-(chloromethyl)pyridin-2-yl)-2-(tetrahydro-2H-pyran-4-yl)ethylcarbamateas the starting material. LC-MS t_(R)=0.792 min in 5-95AB_1.5 minchromatography (MK RP-18e 25-2 mm), MS (ESI) m/z 396.9 [M+H]⁺.

Step 11:(S)-6-(tert-butoxycarbonyl)-7-((tetrahydro-2H-pyran-4-yl)methyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-3-carboxylicacid

Procedure same as that for(S)-6-(tert-butoxycarbonyl)-7-isopropyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-3-carboxylicacid with (S)-tert-butyl3-bromo-7-((tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrrolo[3,4-b]pyridine-6(7H)-carboxylateas the starting material. LC-MS t_(R)=0.990 min in 10-80AB_2.0 minchromatography (Xtimate 3 um, C18, 2.1*30 mm), MS (ESI) m/z 363.1[M+1]⁺.

Preparation A5:(S)-7-benzyl-6-(tert-butoxycarbonyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-3-carboxylicacid

Step 1: (S)-methyl 4-(tert-butoxycarbonylamino)-3-oxo-5-phenylpentanoate

Procedure same as that for ethyl(S)-4-((tert-butoxycarbonyl)amino)-5-methyl-3-oxohexanoate with(S)-2-(tert-butoxycarbonylamino)-3-phenylpropanoic acid as the startingmaterial.

Step 2: (S)-methyl2-(1-(tert-butoxycarbonylamino)-2-phenylethyl)-5-chloronicotinate

Procedure same as that for(S)-2-(1-((tert-butoxycarbonyl)amino)-2-methylpropyl)-5-chloronicotinatewith (S)-methyl 4-(tert-butoxycarbonylamino)-3-oxo-5-phenylpentanoate asthe starting material. LC-MS t_(R)=1.007 min in 5-95AB_1.5 minchromatography (MK RP18e 25-2 mm), MS (ESI) m/z 335.1 [M−55]⁺.

Step 3: (S)-tert-butyl1-(5-chloro-3-(hydroxymethyl)pyridin-2-yl)-2-phenylethylcarbamate

Procedure same as that for tert-butyl(S)-(1-(5-chloro-3-(hydroxymethyl)pyridin-2-yl)-2-methylpropyl)carbamatewith (S)-methyl2-(1-(tert-butoxycarbonylamino)-2-phenylethyl)-5-chloronicotinate as thestarting material. LC-MS t_(R)=0.812 min in 5-95AB_1.5 minchromatography (MK RP18e 25-2 mm), MS (ESI) m/z 362.9, 306.8 [M+H]⁺,[M−55]⁺.

Step 4:(S)-(2-(1-(tert-butoxycarbonylamino)-2-phenylethyl)-5-chloropyridin-3-yl)methyl 4-methylbenzenesulfonate

Procedure same as that for(S)-(2-(1-((tert-butoxycarbonyl)amino)propyl)-5-chloropyridin-3-yl)methyl4-methylbenzenesulfonate with (S)-tert-butyl1-(5-chloro-3-(hydroxymethyl)pyridin-2-yl)-2-phenylethylcarbamate as thestarting material. LC-MS t_(R)=1.069 min in 5-95AB_1.5 minchromatography (MK RP18e 25-2 mm), MS (ESI) m/z 539.1 [M+23]⁺.

Step 5: (S)-tert-butyl7-benzyl-3-chloro-5H-pyrrolo[3,4-b]pyridine-6(7H)-carboxylate

Procedure same as that for tert-butyl(S)-3-chloro-7-isopropyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylatewith(S)-(2-(1-(tert-butoxycarbonylamino)-2-phenylethyl)-5-chloropyridin-3-yl)methyl4-methylbenzenesulfonate as the starting material. LC-MS t_(R)=0.995 minin 5-95AB_1.5 min chromatography (MK RP18e 25-2 mm), MS (ESI) m/z 345.1[M+H]⁺.

Step 6:(S)-7-benzyl-6-(tert-butoxycarbonyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-3-carboxylicacid

Procedure same as that for(S)-6-(tert-butoxycarbonyl)-7-isopropyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-3-carboxylicacid with (S)-tert-butyl7-benzyl-3-chloro-5H-pyrrolo[3,4-b]pyridine-6(7H)-carboxylate as thestarting material. LC-MS t_(R)=0.869 min in 5-95AB_1.5 minchromatography (MK RP18e 25-2 mm), MS (ESI) m/z 355.2 [M+H]⁺.

Preparation A6:6-(tert-butoxycarbonyl)-7-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-3-carboxylicacid

Step 1: methyl 4-(tert-butoxycarbonylamino)-3-oxopentanoate

Procedure same as that for ethyl(S)-4-((tert-butoxycarbonyl)amino)-5-methyl-3-oxohexanoate with2-(tert-butoxycarbonylamino)propanoic acid as the starting material. ¹HNMR (CDCl₃, 400 MHz): δ 5.05-5.26 (m, 1H), 4.28-4.39 (m, 1H), 3.72 (s,3H), 3.50-3.62 (m, 2H), 1.42 (s, 9H), 1.30-1.35 (d, J=7.2 Hz, 3H).

Step 2: methyl 2-(1-(tert-butoxycarbonylamino)ethyl)-5-chloronicotinate

Procedure same as that for(S)-2-(1-((tert-butoxycarbonyl)amino)-2-methylpropyl)-5-chloronicotinatewith methyl 4-(tert-butoxycarbonylamino)-3-oxopentanoate as the startingmaterial. ¹H NMR (CDCl₃, 400 MHz): δ 8.57-8.68 (d, J=2.8 Hz, 1H),8.14-8.24 (d, J=2.4 Hz, 1H), 5.55-5.91 (m, 2H), 3.95 (s, 3H), 1.34-1.47(m, 12H). LCMS t_(R)=1.063 min in 10-80AB_2.0 min chromatography(Xbridge Shield RP18 2.1*50 mm), MS (ESI) m/z 315.1 [M+H]⁺.

Step 3: tert-butyl1-(5-chloro-3-(hydroxymethyl)pyridin-2-yl)ethylcarbamate

Procedure same as that for tert-butyl(S)-(1-(5-chloro-3-(hydroxymethyl)pyridin-2-yl)-2-methylpropyl)carbamatewith methyl 2-(1-(tert-butoxycarbonylamino)ethyl)-5-chloronicotinate asthe starting material. LCMS t_(R)=0.887 min in 10-80AB_2.0 minchromatography (Xbridge Shield RP18 2.1*50 mm), MS (ESI) m/z 287.1[M+H]⁺.

Step 4: tert-butyl1-(5-chloro-3-(chloromethyl)pyridin-2-yl)ethylcarbamate

Procedure same as that for(S)-(2-(1-((tert-butoxycarbonyl)amino)propyl)-5-chloropyridin-3-yl)methyl4-methylbenzenesulfonate with tert-butyl1-(5-chloro-3-(hydroxymethyl)pyridin-2-yl)ethylcarbamate as the startingmaterial. LCMS t_(R)=1.086 min in 10-80AB_2.0 min chromatography(Xbridge Shield RP18 2.1*50 mm), MS (ESI) m/z 305.1 [M+H]⁺.

Step 5: tert-butyl3-chloro-7-methyl-5H-pyrrolo[3,4-b]pyridine-6(7H)-carboxylate

Procedure same as that for tert-butyl(S)-3-chloro-7-isopropyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylatewith tert-butyl 1-(5-chloro-3-(chloromethyl)pyridin-2-yl)ethylcarbamateas the starting material. LCMS t_(R)=1.047 min in 10-80AB_2.0 minchromatography (Xbridge Shield RP18 2.1*50 mm), MS (ESI) m/z 269.1[M+H]⁺.

Step 6:6-(tert-butoxycarbonyl)-7-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-3-carboxylicacid

Procedure same as that for(S)-6-(tert-butoxycarbonyl)-7-isopropyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-3-carboxylicacid with tert-butyl3-chloro-7-methyl-5H-pyrrolo[3,4-b]pyridine-6(7H)-carboxylate as thestarting material. LCMS t_(R)=0.882 min in 10-80AB_2.0 minchromatography (Xbridge Shield RP18 2.1*50 mm), MS (ESI) m/z 279.1[M+H]⁺.

Preparation A7:(R)-6-(tert-butoxycarbonyl)-7-(((tert-butyldimethylsilyl)oxy)methyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-3-carboxylicacid

Step 1:(S)-2-((tert-butoxycarbonyl)amino)-3-((tert-butyldimethylsilyl)oxy)propanoicacid

To a solution of (S)-2-((tert-butoxycarbonyl)amino)-3-hydroxypropanoicacid (30 g, 0.146 mol) in anhydrous DMF (300 mL) was addedtert-butylchlorodimethylsilane (21.90 g, 0.146 mol) and imidazole (19.80g, 0.292 mol) at 0° C., then the mixture was stirred at rt for 18 h. Themixture was diluted with ethyl acetate (300 mL) and water (30 mL),extracted with ethyl acetate (3×300 mL), washed with water (2×1000 mL),brine (2×1000 mL), dried over anhydrous sodium sulfate, filtered andconcentrated to give(S)-2-((tert-butoxycarbonyl)amino)-3-((tert-butyldimethylsilyl)oxy)propanoicacid (34 g, 72%) as a yellow oil. ¹H NMR (CDCl₃, 400 MHz): δ 5.20-5.30(m, 1H), 4.25-4.35 (m, 1H), 4.01-4.15 (m, 1H), 3.75-3.85 (m, 1H), 1.40(s, 9H), 0.82 (s, 9H), 0.01 (s, 6H).

Step 2: (S)-methyl4-((tert-butoxycarbonyl)amino)-5-((tert-butyldimethylsilyl)oxy)-3-oxopentanoate

A mixture of(S)-2-((tert-butoxycarbonyl)amino)-3-((tert-butyldimethylsilyl)oxy)propanoicacid (24.0 g, 75.2 mmol), 1,1′-carbonyldiimidazole (14.6 g, 90.2 mmol)in THF (250 mL) was stirred at rt for 1 h. Then potassium3-methoxy-3-oxopropanoate (11.70 g, 75.2 mmol) and magnesium chloride(7.14 g, 75.2 mmol) were added. After addition, the mixture was stirredat 50° C. for 16 h. TLC (petroleum ether:ethyl acetate=5:1) showed thestarting material was consumed. The mixture was quenched with water (200mL) and extracted with ethyl acetate (3×150 mL). The combined organiclayers were washed with saturated aqueous NaHCO₃ solution (500 mL) andbrine (500 mL), dried over anhydrous sodium sulfate, filtered andconcentrated under reduced pressure to give (S)-methyl4-((tert-butoxycarbonyl)amino)-5-((tert-butyldimethylsilyl)oxy)-3-oxopentanoate(28 g, 100% crude) as a yellow oil, which was used for the next stepdirectly without further purification. LCMS t_(R)=1.282 min in10-80AB_2.0 min chromatography (Xtimate, 2.1*30 mm, 3 um), MS (ESI) m/z276.1 [M−100]⁺.

Step 3: (R)-methyl5-chloro-2-(2,2,3,3,10,10-hexamethyl-8-oxo-4,9-dioxa-7-aza-3-silaundecan-6-yl)nicotinate

To a solution of (S)-methyl4-((tert-butoxycarbonyl)amino)-5-((tert-butyldimethylsilyl)oxy)-3-oxopentanoate(32 g, 85.3 mmol) in THF (320 mL) was added potassium tert-butoxide(10.50 g, 93.8 mmol) at 0° C. After stirring for 45 min, DABCO (10.5 g,93.8 mmol) and 2-chloro-1,3-bis(dimethylamino)trimethiniumhexafluorophosphate (27 g, 89.5 mmol) were added to the mixture at 0° C.The mixture was stirred at rt for 3 h. Ammonium acetate (7.20 g, 93.8mmol) was added to the above solution, and the resulting mixture wasstirred at rt for 18 h. TLC (petroleum ether:ethyl acetate=5:1) showedthe starting material was consumed. The mixture was filtered and thefiltrate was concentrated under reduced pressure. The residue wasdiluted with ethyl acetate (200 mL), washed with water (3×100 mL) andbrine (100 mL), dried over anhydrous sodium sulfate, filtered andconcentrated under reduced pressure. The residue was purified by silicagel chromatography (eluting with petroleum ether:ethyl acetate=10:1,gradient to 8:1) to give (R)-methyl5-chloro-2-(2,2,3,3,10,10-hexamethyl-8-oxo-4,9-dioxa-7-aza-3-silaundecan-6-yl)nicotinate(11 g, 29%) as a white solid. LCMS t_(R)=0.990 min in 10-80AB_2.0 minchromatography (Xtimate, 2.1*30 mm, 3 um), MS (ESI) m/z 445.0 [M+H]⁺.

Step 4: (R)-tert-butyl(2-((tert-butyldimethylsilyl)oxy)-1-(5-chloro-3-(hydroxymethyl)pyridin-2-yl)ethyl)carbamate

To a solution of (R)-methyl5-chloro-2-(2,2,3,3,10,10-hexamethyl-8-oxo-4,9-dioxa-7-aza-3-silaundecan-6-yl)nicotinate(4.0 g, 9.0 mmol) in ethanol (40 mL) was added sodium borohydride (0.66g, 18.0 mmol) and calcium chloride (1.0 g, 9.0 mmol) at 0° C. Themixture was stirred at 0° C. for 2 h. TLC (petroleum ether:ethylacetate=3:1) showed the starting material was consumed. The mixture wasquenched with saturated aqueous NH₄Cl solution (20 mL) and concentratedunder reduced pressure. The residue was extracted with ethyl acetate(3×20 mL). The combined organic layers were washed with brine (20 mL),dried over anhydrous sodium sulfate, filtered and concentrated underreduced pressure to give (R)-tert-butyl(2-((tert-butyldimethylsilyl)oxy)-1-(5-chloro-3-(hydroxymethyl)pyridin-2-yl)ethyl)carbamate(3.45 g, 92%) as a colorless oil, which was used for the next stepdirectly without further purification.

Step 5:(R)-(5-chloro-2-(2,2,3,3,10,10-hexamethyl-8-oxo-4,9-dioxa-7-aza-3-silaundecan-6-yl)pyridin-3-yl)methyl4-methylbenzenesulfonate

To a solution of (R)-tert-butyl(2-((tert-butyldimethylsilyl)oxy)-1-(5-chloro-3-(hydroxymethyl)pyridin-2-yl)ethyl)carbamate(3.45 g, 8.20 mmol) in CH₂Cl₂ (40 mL) was added p-toluenesulfonylchloride (3.15 g, 16.40 mmol) and triethylamine (2.48 g, 24.60 mmol)slowly at 0° C. The mixture was stirred at 0° C. for 1 h. TLC (petroleumether:ethyl acetate=5:1) showed the starting material was consumed. Themixture was quenched with saturated aqueous NaHCO₃ solution (20 mL),extracted with ethyl acetate (3×20 mL) and washed with brine (20 mL).The combined organic layer was dried over anhydrous sodium sulfate,filtered and concentrated under reduced pressure. The residue waspurified by silica gel chromatography (eluting with petroleumether:ethyl acetate=10:1, gradient to 5:1) to give(R)-(5-chloro-2-(2,2,3,3,10,10-hexamethyl-8-oxo-4,9-dioxa-7-aza-3-silaundecan-6-yl)pyridin-3-yl)methyl4-methylbenzenesulfonate (3.15 g, 66%) as a colorless oil. LCMSt_(R)=1.497 min in 10-80AB_2.0 min chromatography (Xtimate, 2.1*30 mm, 3um), MS (ESI) m/z 571.0 [M+H]⁺.

Step 6: (R)-tert-butyl7-(((tert-butyldimethylsilyl)oxy)methyl)-3-chloro-5H-pyrrolo[3,4-b]pyridine-6(7H)-carboxylate

To a solution of(R)-(5-chloro-2-(2,2,3,3,10,10-hexamethyl-8-oxo-4,9-dioxa-7-aza-3-silaundecan-6-yl)pyridin-3-yl)methyl4-methylbenzenesulfonate (3.15 g, 5.5 mmol) in DMF (30 mL) was addedsodium hydride (0.66 g, 16.5 mmol, 60% disperion in mineral oil) at 0°C. The mixture was stirred at 0° C. for 1 h. TLC (petroleum ether:ethylacetate=5:1) showed the starting material was consumed. The mixture wasquenched with saturated aqueous NH₄Cl solution (30 mL) and extractedwith ethyl acetate (3×20 mL). The combined organic layers were washedwith brine (20 mL), dried over anhydrous sodium sulfate, filtered andconcentrated under reduced pressure. The residue was purified by silicagel chromatography (eluting with petroleum ether:ethyl acetate=10:1,gradient to 5:1) to give (R)-tert-butyl7-(((tert-butyldimethylsilyl)oxy)methyl)-3-chloro-5H-pyrrolo[3,4-b]pyridine-6(7H)-carboxylate(1.20 g, 54%) as a colorless oil. LCMS t_(R)=1.323 min in 10-80AB_2.0min chromatography (Xtimate ODS 2.1*30 mm, 3 um), MS (ESI) m/z 343.1[M−55]⁺.

Step 7:(R)-6-(tert-butoxycarbonyl)-7-(((tert-butyldimethylsilyl)oxy)methyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-3-carboxylicacid

Procedure same as that for(S)-6-(tert-butoxycarbonyl)-7-ethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-3-carboxylicacid with (R)-tert-butyl7-(((tert-butyldimethylsilyl)oxy)methyl)-3-chloro-5H-pyrrolo[3,4-b]pyridine-6(7H)-carboxylateas the starting material. LCMS t_(R)=3.835 min in 10-80AB_7.0 minchromatography (Xtimate ODS 2.1*30 mm, 3 um), MS (ESI) m/z 353.1[M−55]⁺. ¹H NMR (CDCl₃, 400 MHz): δ 9.20 (s, 1H), 8.18 (d, J=22.4 Hz,1H), 4.99 (s, 1H), 4.76 (s, 1H), 4.63-4.64 (m, 1H), 4.42-4.63 (m, 1H),4.07-4.12 (m, 1H), 1.53 (s, 9H), 0.65 (s, 9H), 0.07 (s, 3H), 0.18 (s,3H). Basic preparative HPLC method. Mobile phase A: water with 0.05%NH₃H₂O. Mobile phase B: CH₃CN. Flow rate: 80 ml/min. Detection: UV 220nm/254 nm Column: Phenomenex Gemini C18 250*50 mm*Sum. Columntemperature: 30° C. Time in min, % A, % B; 0.00, 55, 35; 30.00, 40, 60;30.20, 0, 100; 35.00, 0, 100.

Preparation A8:(R)-6-(tert-butoxycarbonyl)-7-(methoxymethyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-3-carboxylicacid

Step 1: (R)-tert-butyl3-chloro-7-(hydroxymethyl)-5H-pyrrolo[3,4-b]pyridine-6(7H)-carboxylate

To a solution of (R)-tert-butyl7-(((tert-butyldimethylsilyl)oxy)methyl)-3-chloro-5H-pyrrolo[3,4-b]pyridine-6(7H)-carboxylate(1.0 g, 2.5 mmol) in THF (10 mL) was added dropwise tetrabutylammoniumfluoride (5 mL, 1.0 M in THF). The mixture was stirred at rt for 4 h.LCMS showed the starting material was consumed. The mixture wasconcentrated under reduced pressure. The residue was extracted withethyl acetate (3×10 mL), then the combined organic layer was washed withbrine (20 mL), dried over anhydrous sodium sulfate, filtered andconcentrated under reduced pressure. The residue was purified by silicagel chromatography (petroleum ether:ethyl acetate=10:1, gradient to 1:1)to give (R)-tert-butyl3-chloro-7-(hydroxymethyl)-5H-pyrrolo[3,4-b]pyridine-6(7H)-carboxylate(0.55 g, 77%) as a white solid. LCMS t_(R)=0.712 min in 5-95AB_1.5 minchromatography (RP-18e, 25-2 mm) MS (ESI) m/z 229 [M−55]⁺.

Step 2: (R)-tert-butyl3-chloro-7-(methoxymethyl)-5H-pyrrolo[3,4-b]pyridine-6(7H)-carboxylate

To a solution of (R)-tert-butyl3-chloro-7-(hydroxymethyl)-5H-pyrrolo[3,4-b]pyridine-6(7H)-carboxylate(0.55 g, 1.93 mmol) in CH₃CN (10 mL) was added dropwise silver (I) oxide(2.24 g, 9.68 mmol) and iodomethane (0.60 mL, 9.68 mmol). The mixturewas stirred at rt for 18 h. LCMS showed the starting material wasconsumed. The mixture was filtered and concentrated under reducedpressure. The residue was purified by silica gel chromatography(petroleum ether:ethyl acetate=10:1, gradient to 1:1) to give(R)-tert-butyl3-chloro-7-(methoxymethyl)-5H-pyrrolo[3,4-b]pyridine-6(7H)-carboxylate(0.40 g, 69%) as a yellow solid. LCMS t_(R)=0.725 min in 5-95AB_1.5 minchromatography (RP-18e, 25-2 mm) MS (ESI) m/z 298.9 [M+H]⁺.

Step 3:(R)-6-(tert-butoxycarbonyl)-7-(methoxymethyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-3-carboxylicacid

Procedure same as that for(S)-6-(tert-butoxycarbonyl)-7-ethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-3-carboxylicacid with (R)-tert-butyl3-chloro-7-(methoxymethyl)-5H-pyrrolo[3,4-b]pyridine-6(7H)-carboxylate(400 mg, 1.34 mmol) as the starting material. LCMS t_(R)=0.937 min in10-80AB_2.0 min chromatography (Xtimate ODS 2.1*30 mm, 3 um), MS (ESI)m/z 309.2 [M+H]⁺. HCl preparative HPLC method. Mobile phase A: waterwith 0.05% HCl. Mobile phase B: CH₃CN. Flow rate: 30 mL/min Detection:UV 220 nm/254 nm. Column: Synergi Max-RP 150*30 mm*4 u. Columntemperature: 30° C. Time in min, % A, % B; 0.00, 70, 30; 11.00, 5, 95;11.20, 0, 100; 13.00, 0, 100.

Preparation A9:(R)-6-(tert-butoxycarbonyl)-7-(trifluoromethyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-3-carboxylicacid

Step 1:(R,E)-2-methyl-N-(2,2,2-trifluoroethylidene)propane-2-sulfinamide

To a solution of 2,2,2-trifluoroacetaldehyde (30.0 g, 0.25 mole) inCH₂Cl₂ (300 mL) was added (R)-2-methylpropane-2-sulfinamide (31.20 g,0.25 mole) and MgSO₄ (30 g), then the mixture was stirred at 40° C. for4 h. The mixture was filtered, then 4A MS (120 g) was added to thefiltrate. The mixture was stirred at 40° C. for 18 h. The mixture wasfiltered and the filtrate was concentrated to give(R,E)-2-methyl-N-(2,2,2-trifluoroethylidene)propane-2-sulfinamide (40 g,76% crude) as a white solid. LC-MS t_(R)=0.851 min in 10-80AB_7.0 minchromatography (Xtimate ODS 2.1*30 mm, 3 um), MS (ESI) m/z 202.0 [M+H]⁺.

Step 2:(R)—N—((R)-1-(5-bromo-3-(methoxymethyl)pyridin-2-yl)-2,2,2-trifluoroethyl)-2-methylpropane-2-sulfinamide

To 30 mL of toluene was added n-BuLi (6.0 mL, 1.50 mmol) at −70° C.,followed a solution of 2,5-dibromo-3-(methoxymethyl)pyridine (2.80 g,1.0 mmol) in toluene (10 mL). After being stirred for 30 min, a solutionof (R,E)-2-methyl-N-(2,2,2-trifluoroethylidene)propane-2-sulfinamide(3.35 g, 1.0 mmol, 60% purity) in toluene (10 mL) was added to themixture. The resulting mixture was stirred at −70° C. for 2 h. Saturatedaqueous NH₄Cl solution (20 mL) was added to the mixture, followed byextraction with ethyl acetate (3×20 mL). The combined organic layerswere washed with brine (20 mL), dried over anhydrous sodium sulfate,filtered and concentrated under reduced pressure. The residue waspurified by silica gel chromatography (eluting with petroleumether:ethyl acetate=5:1, gradient to 3:1) to give(R)—N—((R)-1-(5-bromo-3-(methoxymethyl)pyridin-2-yl)-2,2,2-trifluoroethyl)-2-methylpropane-2-sulfinamide(1.60 g, 39%) as an oil. LC-MS t_(R)=1.105 min in 10-80AB_2.0 minchromatography (Xtimate, 2.1*30 mm, 3 um), MS (ESI) m/z 402.9 [M+H]⁺.

Step 3:(R)-(2-(1-amino-2,2,2-trifluoroethyl)-5-bromopyridin-3-yl)methanol

To a solution of(R)—N—((R)-1-(5-bromo-3-(methoxymethyl)pyridin-2-yl)-2,2,2-trifluoroethyl)-2-methylpropane-2-sulfinamide(0.75 g, 1.86 mmol) in CH₂Cl₂ (10 mL) was added boron tribromide (2.33g, 9.32 mmol) at −78° C. The mixture was stirred at rt for 18 h.Methanol (10 mL) was added to the mixture slowly. The mixture wasconcentrated under reduced pressure to give(R)-(2-(1-amino-2,2,2-trifluoroethyl)-5-bromopyridin-3-yl)methanol(0.529 g, 100% crude) as a yellow oil which was used in the next stepdirectly. LC-MS t_(R)=1.306 min in 10-80 CD_POS (Xtimate ODS 2.1*30 mm,3 um), MS (ESI) m/z 284.9 [M+H]⁺.

Step 4: (R)-tert-butyl(1-(5-bromo-3-(hydroxymethyl)pyridin-2-yl)-2,2,2-trifluoroethyl)carbamate

A mixture of(R)-(2-(1-amino-2,2,2-trifluoroethyl)-5-bromopyridin-3-yl)methanol (529mg, 1.86 mmol), di-tert-butyl dicarbonate (0.814 g, 3.73 mmol) andtriethylamine (0.939 g, 9.30 mmol) in MeOH (10 mL) was stirred at rt for18 h. The mixture was concentrated under reduced pressure. The residuewas purified by silica gel chromatography (eluting with petroleumether:ethyl acetate=10:1, gradient to 5:1) to give (R)-tert-butyl(1-(5-bromo-3-(hydroxymethyl)pyridin-2-yl)-2,2,2-trifluoroethyl)carbamate(510 mg, 71%) as a white solid. LC-MS t_(R)=1.036 min in 10-80AB_2.0 minchromatography (Xtimate ODS 2.1*30 mm, 3 um), MS (ESI) m/z 385.0 [M+H]⁺.

Step 5:(R)-(5-bromo-2-(1-((tert-butoxycarbonyl)amino)-2,2,2-trifluoroethyl)pyridin-3-yl)methylmethanesulfonate & (R)-tert-butyl(1-(5-bromo-3-(chloromethyl)pyridin-2-yl)-2,2,2-trifluoroethyl)carbamate

To a solution of (R)-tert-butyl(1-(5-bromo-3-(hydroxymethyl)pyridin-2-yl)-2,2,2-trifluoroethyl)carbamate(510 mg, 1.32 mmol) and triethylamine (0.91 mL, 6.60 mmol) in CH₂Cl₂ (10mL) was added methanesulfonyl chloride (302 mg, 2.64 mmol) at 0° C. Themixture was stirred at rt for 18 h. LCMS showed the starting materialwas consumed. The reaction mixture was quenched with H₂O (10 mL), thenextracted with CH₂Cl₂ (3×10 mL). The combined organic layers were washedwith brine (20 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure. The residue was purified by silicagel chromatography (eluting with petroleum ether:ethyl acetate=10:1,gradient to 5:1) to give(R)-(5-bromo-2-(1-((tert-butoxycarbonyl)amino)-2,2,2-trifluoroethyl)pyridin-3-yl)methylmethanesulfonate (150 mg, 25%) as a white solid and (R)-tert-butyl(1-(5-bromo-3-(chloromethyl)pyridin-2-yl)-2,2,2-trifluoroethyl)carbamate(350 mg, 66%) as a white solid. LC-MS t_(R)=1.265 min in 10-80AB_2.0 minchromatography (Xtimate, 2.1*30 mm, 3 um), MS (ESI) m/z 347.0 [M+H]⁺.

Step 6: (R)-tert-butyl3-bromo-7-(trifluoromethyl)-5H-pyrrolo[3,4-b]pyridine-6(7H)-carboxylate

To a solution of (R)-tert-butyl(1-(5-bromo-3-(chloromethyl)pyridin-2-yl)-2,2,2-trifluoroethyl)carbamate(350 mg, 0.87 mmol) in DMF (10 mL) was added sodium hydride (104 mg,2.61 mmol, 60% dispersion in mineral oil) at 0° C. The mixture wasstirred at 0° C. for 1 h. The mixture was quenched with water (10 mL)and extracted with ethyl acetate (3×10 mL). The combined organic layerwas washed with brine (20 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure. The residue was purified by silicagel chromatography (eluting with petroleum ether:ethyl acetate=10:1,gradient to 8:1) to give (R)-tert-butyl3-bromo-7-(trifluoromethyl)-5H-pyrrolo[3,4-b]pyridine-6(7H)-carboxylate(170 mg, 53%) as a white solid. LC-MS t_(R)=1.097 min in 10-80AB_2.0 minchromatography (Xtimate, 2.1*30 mm, 3 um), MS (ESI) m/z 367.0 [M+H]⁺.SFC t_(R)=1.491 min (major), 1.778 min in 12.0 min chromatography(Column: AD-3_B3_5_40_25 ML), ee=67.2%.

Step 7:(R)-6-(tert-butoxycarbonyl)-7-(trifluoromethyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-3-carboxylicacid

Procedure same as that for(S)-6-(tert-butoxycarbonyl)-7-ethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-3-carboxylicacid with (R)-tert-butyl3-bromo-7-(trifluoromethyl)-5H-pyrrolo[3,4-b]pyridine-6(7H)-carboxylateas the starting material. LC-MS t_(R)=2.466 min in 10-80AB_7.0 minchromatography (Xtimate ODS 2.1*30 mm, 3 um), MS (ESI) m/z 333.1 [M+H]⁺.HCl preparative HPLC method. Mobile phase A: water with 0.05% HCl.Mobile phase B: CH₃CN. Flow rate: 30 mL/min. Detection: UV 220 nm/254 nmColumn: Synergi Max-RP 150*30 mm*4 um. Column temperature: 30° C. Timein min, % A, % B; 0.00, 60, 40; 8.00, 30, 70; 8.20, 0, 100; 10.00, 0,100.

Preparation B1: (R)-2-amino-2-(4-(ethylsulfonyl)phenyl)ethanol

Step 1: (4-bromophenyl)(ethyl)sulfane

A mixture of 4-bromobenzenethiol (50 g, 0.26 mol), bromoethane (58 g,0.53 mol) and triethylamine (78 g, 0.78 mol) in acetonitrile (1 L) wasstirred at reflux for 17 h. The mixture was cooled to rt and filtered.The filtrate was concentrated under vacuum. The residue was purified bysilica gel chromatography (eluting with petroleum ether) to give(4-bromophenyl)(ethyl)sulfane (55 g, 96%) as an oil. ¹H NMR (CDCl₃, 400MHz): δ 7.40-7.42 (dd, J=6.4, 2.0 Hz, 2H), 7.18-7.20 (dd, J=6.4, 2.0 Hz,2H), 2.91-2.96 (q, J=7.2 Hz, 2H), 1.30-1.33 (t, J=7.2 Hz, 3H).

Step 2: 2-((tert-butyldimethylsilyl)oxy)ethanol

To a solution of ethane-1,2-diol (110 g, 1.77 mol) in anhydrous CH₂Cl₂(1.1 L) was added triethylamine (215.2 g, 296 mL, 2.13 mol) at rt. Themixture was cooled to 0° C., then tert-butylchlorodimethylsilane (267.1g, 1.77 mol) dissolved in CH₂Cl₂ (300 mL) was added dropwise over 1 h.The mixture was stirred at rt overnight. The reaction mixture wasquenched with saturated aqueous NH₄Cl solution (400 mL) and separated.The aqueous phase was extracted with MTBE (2×400 mL). The combinedorganic layers were concentrated under vacuum and the residue wasredissolved in MTBE (400 mL). The MTBE layer was washed with water(2×500 mL) and brine (500 mL), dried over anhydrous sodium sulfate,filtered and concentrated under vacuum to give2-((tert-butyldimethylsilyl)oxy)ethanol (280 g, 90%) as a slight oil,which was used for the next step directly without further purification.¹H NMR (CDCl₃, 400 MHz): δ 3.64-3.66 (m, 2H), 3.57-3.60 (m, 2H), 0.85(s, 9H), 0.02 (s, 6H).

Step 3: 2-((tert-butyldimethylsilyl)oxy)acetaldehyde

To a solution of CH₂Cl₂ (1.8 L) cooled to −30° C. was added oxalylchloride (79.2 g, 52.8 mL, 624 mmol) dropwise. The mixture was cooled to−78° C., then DMSO (62.5 g, 88.5 mL, 1.25 mmol) was added dropwise.After addition, the mixture was stirred at −78° C. for 30 min. Asolution of 2-((tert-butyldimethylsilyl)oxy)ethanol (100 g, 567 mmol)dissolved in CH₂Cl₂ (200 mL) was added slowly at −78° C. The reactionmixture was stirred at −78° C. for 1 h. Triethylamine (287 g, 395 mL,2.84 mmol) was added dropwise at −78° C. The mixture was stirred at −78°C. for 30 min and then rt overnight. The reaction mixture was washedwith water (1 L), 1 N HCl (2×1 L), saturated aqueous NaHCO₃ solution (1L) and brine (1 L). The organic layer was dried over anhydrous sodiumsulfate, filtered and concentrated under vacuum to give2-((tert-butyldimethylsilyl)oxy)acetaldehyde (98.5 g, 99.8%) as a brownoil, which was used for the next step directly without furtherpurification. ¹H NMR (CDCl₃, 400 MHz): δ 9.70 (s, 1H), 4.22 (s, 2H),0.93 (s, 9H), 0.11 (s, 6H).

Step 4:(R,E)-N-(2-((tert-butyldimethylsilyl)oxy)ethylidene)-2-methylpropane-2-sulfinamide

A mixture of 2-((tert-butyldimethylsilyl)oxy)acetaldehyde (93.5 g, 0.54mol), (R)-2-methylpropane-2-sulfinamide (78.8 g, 0.65 mol) and copper(II) sulfate (215 g, 1.35 mol) in anhydrous CH₂Cl₂ (1.5 L) was stirredat rt for 16 h. The mixture was quenched with H₂O (800 mL) andseparated. The aqueous phase was extracted with CH₂Cl₂ (2×1 L). Thecombined organic layers were washed with water (1 L) and brine (1 L),dried over anhydrous sodium sulfate, filtered and concentrated undervacuum. The residue was purified by silica gel chromatography (elutingwith petroleum ether:ethyl acetate=8:1) to give(R,E)-N-(2-((tert-butyldimethylsilyl)oxy)ethylidene)-2-methylpropane-2-sulfinamide(38.5 g, 26%) as a yellow oil. ¹H NMR (CDCl₃, 400 MHz): δ 7.96-7.97 (t,J=3.2 Hz, 1H), 4.44-4.45 (d, J=2.8 Hz, 2H), 1.11 (s, 9H), 0.00 (s, 6H).

Step 5:(R)—N—((R)-2-((tert-butyldimethylsilyl)oxy)-1-(4-(ethylthio)phenyl)ethyl)-2-methylpropane-2-sulfinamide

To a solution of (4-bromophenyl)(ethyl)sulfane (28.9 g, 133.1 mmol) inanhydrous THF (500 mL) was added dropwise n-butyllithium (73 mL, 181.5mmol, 2.5 M in hexanes) at −78° C. The mixture was stirred at −78° C.for 30 min. A solution of(R,E)-N-(2-((tert-butyldimethylsilyl)oxy)ethylidene)-2-methylpropane-2-sulfinamide(33.5 g, 121 mmol) in anhydrous THF (100 mL) was added to the mixture at−78° C. The mixture was stirred at −78° C. for 2 h, then allowed to warmto rt and stirred for 2 h. The mixture was quenched with saturatedaqueous NH₄Cl solution (200 mL) and extracted with ethyl acetate (3×300mL). The combined organic layer was washed with water (200 mL) and brine(200 mL), dried over anhydrous Na₂SO₄, filtered and concentrated undervacuum. The residue was purified by silica gel chromatography (elutingwith petroleum ether:ethyl acetate=15:1) three times to afford(R)—N—((R)-2-((tert-butyldimethylsilyl)oxy)-1-(4-(ethylthio)phenyl)ethyl)-2-methylpropane-2-sulfinamide(22 g, 44%) as a yellow oil. ¹H NMR (CDCl₃, 400 MHz): δ 7.21-7.24 (d,J=7.2 Hz, 2H), 7.18-7.21 (d, J=8.4 Hz, 2H), 4.42-4.45 (dd, J=8.8, 2.4Hz, 1H), 4.21 (brs, 1H), 3.69-3.73 (dd, J=10.4, 4.4 Hz, 1H), 3.51-3.56(t, J=9.6 Hz, 1H), 2.87-2.92 (q, J=7.6 Hz, 2H), 1.25-1.29 (t, J=7.2 Hz,3H), 1.18 (s, 9H), 0.88 (s, 9H), 0.02 (s, 6H). LCMS t_(R)=1.010 min in5-95AB_1.5 min chromatography (MK RP18e 25-2 mm), MS (ESI) m/z 437.9[M+Na]⁺. Isomer SFC t_(R)=3.607 and 4.014 min in 12 min chromatography(AD-H_5_5_40_2.3 5 ML), ee=90.85%.

Step 6: (R)-2-amino-2-(4-(ethylthio)phenyl)ethanol

To a solution of(R)—N—((R)-2-((tert-butyldimethylsilyl)oxy)-1-(4-(ethylthio)phenyl)ethyl)-2-methylpropane-2-sulfinamide(22 g, 52.9 mmol) in CH₂Cl₂ (250 mL) was added HCl (26.5 mL, 4 N indioxane) at 0° C. The mixture was stirred at rt for 2 h. LCMS showed nostarting material remaining. The mixture was concentrated under reducedpressure to afford crude (R)-2-amino-2-(4-(ethylthio)phenyl)ethanol HClsalt (12.3 g, 100%) as a brown solid, which was used for the next stepdirectly without further purification. LCMS t_(R)=1.226 min in 0-30AB_2min chromatography (Xtimate 3 um, C18, 2.1*30 mm), MS (ESI) m/z 180.9[M−OH]⁺.

Step 7: (R)-2-amino-2-(4-(ethylsulfonyl)phenyl)ethanol

To a mixture of (R)-2-amino-2-(4-(ethylthio)phenyl)ethanol (15.2 g, 65.0mmol) in methanol (200 mL) was added dropwise a solution of oxonereagent (80.0 g, 130.0 mmol) in water (200 mL) at 0° C. The mixture wasstirred at rt for 1.5 h; LCMS showed no starting material remaining. Themixture was filtered and methanol was removed under reduced pressure.The aqueous phase was extracted with EtOAc (2×80 mL), then the aqueouslayer was basified to pH=8-9 with solid sodium carbonate portionwise at0° C., then this solution was lyophilized (contained the Na₂CO₃). Thesolid was dissolved in CH₂Cl₂:MeOH (3:1, 600 mL) and stirred for 30 min,filtered, then concentrated under reduced pressure. The residue waspurified by silica gel chromatography (eluting with CH₂Cl₂:MeOH=1:0 to4:1) to give (R)-2-amino-2-(4-(ethylsulfonyl)phenyl)ethanol (11.5 g,77%) as a white solid. LC-MS t_(R)=0.738 min in 0-30CD_POSchromatography (Xtimate ODS 2.1*30 mm, 3 um), MS (ESI) m/z 230.1 [M+H]⁺.Isomer SFC t_(R)=6.99 min in 30 min chromatography (CD-PH_10-80_B_08ML), ee=97.42%. ¹H NMR (D₂O, 400 MHz): δ 7.82-7.84 (d, J=8.0 Hz, 2H),7.54-7.56 (d, J=8.4 Hz, 2H), 4.33-4.35 (t, J=6.4 Hz, 1H), 3.72-3.78 (m,2H), 3.19-3.25 (q, J=7.6 Hz, 2H), 1.03-1.07 (t, J=7.6 Hz, 3H).

Alternate Preparation for B1

Step 1: 4-(ethylsulfonyl)benzaldehyde

To a solution of 4-fluorobenzaldehyde (24.6 g, 198 mmol) indimethylsulfoxide (60 mL) was added sodium ethanesulfinate (46 g, 396mmol). The resulting mixture was stirred at 125° C. for 20 h. Aftercooling to rt, the reaction mixture was triturated with 350 mL of H₂O.The product was filtered, washed with two 10-mL portions of EtOH anddried under vacuum to afford 4-(ethylsulfonyl)benzaldehyde as a lightyellow solid (31.2 g, 80% yield). LC-MS t_(R)=1.19 min in 2 minchromatography, MS (ESI) m/z 199.1 [M+H]⁺. ¹H NMR (CDCl₃) δ 10.14 (s,1H), 8.09 (s, 4H), 3.16 (q, J=7.2 Hz, 2H), 1.30 (t, J=7.2 Hz, 3H).

Step 2: 2-(4-(ethylsulfonyl)phenyl)oxirane

To a solution of 4-(ethylsulfonyl)benzaldehyde (10 g, 50.5 mmol) in DMF(85 mL) at rt was added trimethylsulfonium iodide (11.9 g, 58.1 mmol)followed by potassium hydroxide powder (5.66 g, 101 mmol). The reactionmixture was stirred at rt for 20 min before quenching with H₂O (50 mL).The mixture was carefully neutralized with 1 N HCl solution (55 mL) andextracted with ethyl acetate (3×100 mL). The combined organic phase waswashed with brine, dried over anhydrous Na₂SO₄, and passed through a padof silica gel (eluting with ethyl acetate). It was concentrated underreduced pressure to afford crude 2-(4-(ethylsulfonyl)phenyl)oxirane asyellow oil, which was used directly for the next step without furtherpurification. LC-MS t_(R)=1.13 min in 2 min chromatography, MS (ESI) m/z213.2 [M+H]⁺.

Step 3: 2-amino-2-(4-(ethylsulfonyl)phenyl)ethan-1-ol

To a solution of crude 2-(4-(ethylsulfonyl)phenyl)oxirane (50.5 mmol) inCH₃CN (200 mL) at 0° C. was slowly added concentrated sulfuric acid (5.4mL, 101 mmol). The mixture was allowed to stir at rt for 1.5 h. LCMSshowed the starting material was consumed. H₂O (15 mL) was added to thereaction mixture. Stirring continued at rt for 8 h, then at 45° C. for10 h. After cooling to rt, the pH of the reaction mixture was adjustedto 3-4 by addition of 1 N NaOH solution (90 mL). The mixture wasextracted with ethyl acetate (100 mL). The organic phase was thenextracted with H₂O (2×30 mL). The combined aqueous layers were thenbasified with 1 N NaOH solution (110 mL) to pH=9 and extracted with1-butanol (5×60 mL). The combined organic layer (consisting of 1-butanolextracts) was dried over anhydrous Na₂SO₄, filtered and concentratedunder reduced pressure. It was dried under high vacuum to afford crude2-amino-2-(4-(ethylsulfonyl)phenyl)ethan-1-ol as an off-white solid. 4g, 35% yield over 3 steps. Intermediate4-(4-(ethylsulfonyl)phenyl)-2-methyl-4,5-dihydrooxazole: LC-MSt_(R)=0.77, 0.81 min in 2 min chromatography, MS (ESI) m/z 254.26[M+H]⁺. 2-amino-2-(4-(ethylsulfonyl)phenyl)ethan-1-ol: LC-MS t_(R)=0.61min in 2 min chromatography, MS (ESI) m/z 230.21 [M+H]⁺. ¹H NMR (CD₃OD):δ 7.88 (d, J=8.4 Hz, 2H), 7.64 (d, J=8.4 Hz, 2H), 4.16-4.12 (m, 1H),3.76-3.72 (m, 1H), 3.66-3.61 (m, 1H), 3.17 (q, J=7.2 Hz, 2H), 1.19 (t,J=7.2 Hz, 3H).

Step 4: 2-amino-2-(4-(ethylsulfonyl)phenyl)ethan-1-ol mono-mandelatesalt

To a solution of 2-amino-2-(4-(ethylsulfonyl)phenyl)ethan-1-ol (238 mg,1.0 mmol) in MeOH (3 mL) at 50° C. was added a solution of (R)-Mandelicacid (76 mg, 0.5 mmol) in MeOH (1 mL). The resulting solution wasallowed to cool down to ambient temperature slowly. After stirring for 1day, the resulting crystals were collected by vacuum filtration anddried under high vacuum, providing the mono-mandelate salt as a whitecrystal, 107 mg (28% yield), 92.5% ee. ¹H NMR (CD₃OD): δ 7.97 (d, J=8.0Hz, 2H), 7.71 (d, J=8.4 Hz, 2H), 7.46 (d, J=8.0 Hz, 2H), 7.46 (d, J=8.0Hz, 2H), 7.31-7.27 (m, 2H), 7.25-7.22 (m, 1H), 4.42-4.42 (m, 1H),3.92-3.89 (m, 1H), 3.81-3.77 (m, 1H), 3.21 (q, J=7.2 Hz, 2H), 1.21 (t,J=7.2 Hz, 3H).

Preparation B2: (1R,2R)-1-amino-1-(4-(ethylsulfonyl)phenyl)propan-2-oland (1S,2S)-1-amino-1-(4-(ethylsulfonyl)phenyl)propan-2-ol

Step 1: 1-bromo-4-(ethylsulfonyl)benzene

To a solution of (4-bromophenyl)(ethyl)sulfane (5 g, 23.15 mmol) inacetonitrile (50 mL) was added water (50 mL) and oxone (28.94 g, 46.30mmol). The mixture was stirred at rt for 1 h. TLC (petroleum ether:ethylacetate=10:1) showed that the starting material was completely consumed.The reaction mixture was quenched with saturated aqueous sodium sulfite(150 mL) and extracted with EtOAc (3×50 mL). The combined organic layerswere washed with water (100 mL), dried over anhydrous Na₂SO₄, filteredand concentrated under reduced pressure. The residue was purified bysilica gel chromatography eluting with petroleum ether:ethyl acetate10:1 to 2:1 to afford 1-bromo-4-(ethylsulfonyl)benzene (5.2 g, 90%) as awhite solid. ¹H NMR (CDCl₃, 400 MHz): δ 7.73 (dd, J=8.4, 18.0 Hz, 4H),3.10 (q, J=7.2 Hz, 2H), 1.26 (t, J=7.2 Hz, 3H).

Step 2: (E)-1-(ethylsulfonyl)-4-(prop-1-en-1-yl)benzene

To a solution of 1-bromo-4-(ethylsulfonyl)benzene (572 mg, 2.3 mmol) indioxane (20 mL) was added potassium (E)-propenyl-1-trifluoroborate (375mg, 2.53 mmol), cesium carbonate (1.5 g, 4.6 mmol), water (4 mL) andpalladium (II) acetate (57 mg, 0.25 mmol). The mixture was stirred at100° C. for 16 h. The mixture was filtered, then the filtrate wasconcentrated under reduced pressure. The residue was purified by silicagel chromatography eluting with petroleum ether:ethyl acetate 10:1 to5:1 to afford (E)-1-(ethylsulfonyl)-4-(prop-1-en-1-yl)benzene (410 mg,85%) as a white solid. ¹H NMR (CDCl₃, 400 MHz): δ 7.80 (d, J=8.4 Hz,2H), 7.47 (d, J=8.4 Hz, 2H), 6.50-6.35 (m, 2H), 3.10 (q, J=7.6 Hz, 2H),1.93 (d, J=4.8 Hz, 3H), 1.26 (t, J=7.6 Hz, 3H).

Step 3: tert-butyl((1R,2R)-1-(4-(ethylsulfonyl)phenyl)-2-hydroxypropyl)carbamate andtert-butyl((1S,2S)-1-(4-(ethylsulfonyl)phenyl)-2-hydroxypropyl)carbamate

To a solution of tert-butyl carbamate (708 mg, 6.05 mmol) in 1-propanol(15 mL) was added aqueous NaOH solution (14 mL, 0.38 M). The mixture wasstirred at rt for 5 min, then1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione (797 mg, 2.93 mmol) wasadded. The mixture was stirred at rt for 10 min Solutions of (DHQ)₂-PHAL(92 mg, 0.12 mmol) in 1-propanol (1 mL),(E)-1-(ethylsulfonyl)-4-(prop-1-en-1-yl)benzene (410 mg, 1.95 mmol) in1-propanol (2 mL), and K₂OsO₄.H₂O (29 mg, 0.08 mmol) in aq. NaOHsolution (0.2 mL, 0.38 M) were added successively to the reactionmixture at 0° C. The mixture was stirred at rt for 16 h. The mixture wasdiluted with water (100 mL) and extracted with EtOAc (3×50 mL). Thecombined organic layers were dried over anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure. The residue was purified bychromatography column on silica gel eluting with petroleum ether:ethylacetate 10:1 to 1:1 and preparative TLC (petroleum ether:ethylacetate=1:1) to afford a mixture of tert-butyl((1R,2R)-1-(4-(ethylsulfonyl)phenyl)-2-hydroxypropyl)carbamate andtert-butyl((1S,2S)-1-(4-(ethylsulfonyl)phenyl)-2-hydroxypropyl)carbamate (175 mg,26%) as a white solid. LCMS t_(R)=0.774 min in 5-95AB_1.5 minchromatography (Welch MK RP-18e, 25-2 mm), MS (ESI) m/z 366.1 [M+Na]⁺.¹H NMR (CDCl₃ 400 MHz): δ 7.86 (d, J=8.4 Hz, 2H), 7.50 (d, J=8.4 Hz,2H), 5.60-5.50 (m, 1H), 4.75-4.60 (m, 1H), 4.13-4.02 (m, 1H), 3.10 (q,J=7.6 Hz, 2H), 1.43 (s, 9H), 1.35-1.25 (m, 6H).

Step 4: (1R,2R)-1-amino-1-(4-(ethylsulfonyl)phenyl)propan-2-ol and(1S,2S)-1-amino-1-(4-(ethylsulfonyl)phenyl)propan-2-ol

Procedure same as that for(S)—N—((S)-1-(4-(ethylsulfonyl)phenyl)-2-hydroxyethyl)-7-isopropyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-3-carboxamidewith a mixture of tert-butyl((1R,2R)-1-(4-(ethylsulfonyl)phenyl)-2-hydroxypropyl)carbamate andtert-butyl((1S,2S)-1-(4-(ethylsulfonyl)phenyl)-2-hydroxypropyl)carbamate as thestarting materials.

Preparation B3: (1R,2S)-1-amino-1-(4-(ethylsulfonyl)phenyl)propan-2-ol &(1S,2R)-1-amino-1-(4-(ethylsulfonyl)phenyl)propan-2-ol

Step 1: (2S,3S)-2-(4-(ethylsulfonyl)phenyl)-3-methyloxirane and(2R,3R)-2-(4-(ethylsulfonyl)phenyl)-3-methyloxirane

To a solution of (E)-1-(ethylsulfonyl)-4-(prop-1-en-1-yl)benzene (200mg, 0.95 mmol) in CH₂Cl₂ (10 mL) was added m-chloroperbenzoic acid (500mg, 2.86 mmol). The mixture was stirred at 18° C. for 20 h. TLC(petroleum ether:ethyl acetate=3:1) showed that the starting materialwas consumed completely. The reaction solution was quenched withsaturated aqueous sodium sulfite solution (40 mL) and extracted withCH₂Cl₂ (3×15 mL). The combined organic layers were dried over anhydrousNa₂SO₄, filtered and concentrated under reduced pressure. The residuewas purified by silica gel chromatography eluting with petroleumether:ethyl acetate 15:1 to 3:1 to afford a mixture of(2S,3S)-2-(4-(ethylsulfonyl)phenyl)-3-methyloxirane and(2R,3R)-2-(4-(ethylsulfonyl)phenyl)-3-methyloxirane (180 mg, 80%) as acolorless oil. ¹H NMR (CDCl₃, 400 MHz): δ 7.85 (d, J=8.4 Hz, 2H), 7.44(d, J=8.4 Hz, 2H), 3.64 (d, J=1.6 Hz, 1H), 3.09 (q, J=7.6 Hz, 2H), 3.00(dd, J=2.0, 5.2 Hz, 1H), 1.47 (d, J=5.2 Hz, 3H), 1.25 (t, J=7.6 Hz, 3H).

Step 2: (1R,2S)-1-amino-1-(4-(ethylsulfonyl)phenyl)propan-2-ol and(1S,2R)-1-amino-1-(4-(ethylsulfonyl)phenyl)propan-2-ol

To a mixture of (2S,3S)-2-(4-(ethylsulfonyl)phenyl)-3-methyloxirane and(2R,3R)-2-(4-(ethylsulfonyl)phenyl)-3-methyloxirane (120 mg, 0.53 mmol)in i-PrOH (4 mL) was added ammonium hydroxide (4 mL). The mixture wasstirred at 110° C. in a sealed tube for 17 h. LCMS showed that thereaction was complete. The mixture was concentrated under reducedpressure and then lyophilized to remove excess ammonium hydroxide toafford a crude mixture of(1R,2S)-1-amino-1-(4-(ethylsulfonyl)phenyl)propan-2-ol and(1S,2R)-1-amino-1-(4-(ethylsulfonyl)phenyl)propan-2-ol (120 mg, 100%) asa yellow oil, which was used for the next step directly without furtherpurification.

LCMS t_(R)=0.338 min in 0-30AB_2 min chromatography (Welch Xtimate 3 um,C18, 2.1*30 mm), MS (ESI) m/z 243.9 [M+H]⁺.

Preparation B4: 2-amino-2-(4-(ethylthio)phenyl)propan-1-ol

Step 1: ethyl 2-(4-(ethylthio)phenyl)-2-oxoacetate

To a mixture of aluminum chloride (47.6 g, 357 mmol) in dichloromethane(200 mL) at 0° C. was added ethyl 2-chloro-2-oxoacetate (31.9 mL, 286mmol) slowly. After stirring for 20 min, a solution of ethyl phenylsulfide (32.80 g, 238 mmol) in dichloromethane (200 mL) was addeddropwise at 0° C. After the addition, the mixture was stirred at 0° C.for 30 min before warming to rt and stirring for 2.5 h. LCMS showed thatthe reaction was complete. The reaction mixture was quenched by ice,diluted with ethyl acetate (800 mL), then washed successively with water(250 mL) and brine (100 mL). It was dried over Na₂SO₄, filtered andconcentrated by rotary evaporation to afford 52.41 g (93% yield) ofcrude ethyl 2-(4-(ethylthio)phenyl)-2-oxoacetate as a yellowish oil,which was used without further purification. LCMS t_(R)=1.77 min in 2min chromatography, MS (ESI) m/z 239 [M+H]⁺.

Step 2: ethyl(R,E)-2-((tert-butylsulfinyl)imino)-2-(4-(ethylthio)phenyl)acetate

To a mixture of ethyl 2-(4-(ethylthio)phenyl)-2-oxoacetate (20 g, 84.3mmol) in dry THF (100 mL) was added (R)-2-methylpropane-2-sulfinamide(11.18 g, 92.7 mmol) and titanium (IV) ethoxide (28.74 g, 126 mmol). Themixture was heated at reflux overnight. The solution color graduallyturned into a light brown. After cooling to rt, the reaction mixture wasquenched with brine (25 mL) and stirred for 30 min. It was then filteredthrough a pad of Celite, rinsing the solid with ethyl acetate (100 mL).The filtrate was washed with water (50 mL) and brine (25 mL), then theorganic phase was dried over Na₂SO₄, filtered, and concentrated byrotary evaporation to afford 23.09 g (80.6% yield) of crude ethyl(R,E)-2-((tert-butylsulfinyl)imino)-2-(4-(ethylthio)phenyl)acetate as alight brown oil, which was used without further purification. LCMSt_(R)=1.81 min in 2 min chromatography, MS (ESI) m/z 342 [M+H]⁺.

Step 3: ethyl(R)-2-(((R)-tert-butylsulfinyl)amino)-2-(4-(ethylthio)phenyl)propanoate

To a mixture of ethyl(R,E)-2-((tert-butylsulfinyl)imino)-2-(4-(ethylthio)phenyl)acetate (100mg, 0.293 mmol), in dry THF (4 mL) at 0° C. was added dimethyl zinc (2.0M in toluene, 161 μL, 0.322 mmol). After stirring for 10 min,methylmagnesium bromide (1.4 M in toluene/THF, 2.46 mL, 3.44 mmol) wasadded dropwise. The mixture was stirred at 0° C. for 20 min beforewarming to rt and stirring for 16 h. The reaction mixture was quenchedwith saturated aqueous ammonium chloride solution (15 mL), then dilutedwith ethyl acetate (50 mL). The organic layer was washed with 0.5%aqueous HCl (20 mL) and brine (10 mL), dried over Na₂SO₄, filtered andconcentrated by rotary evaporation. The residue was purified by silicagel chromatography (100% hexanes, gradient to 1:1 hexanes:ethyl acetate)to afford 60 mg (57% yield) of ethyl(R)-2-(((R)-tert-butylsulfinyl)amino)-2-(4-(ethylthio)phenyl)propanoate.LCMS t_(R)=1.61 min in 2 min chromatography, MS (ESI) m/z 358 [M+H]⁺.

Step 4:(R)—N—((R)-2-(4-(ethylthio)phenyl)-1-hydroxypropan-2-yl)-2-methylpropane-2-sulfinamide

To a solution of ethyl(R)-2-(((R)-tert-butylsulfinyl)amino)-2-(4-(ethylthio)phenyl)propanoate(60 mg, 0.168 mmol) in dry THF (3 mL) at 0° C. was added dropwiselithium borohydride (2.0 M in THF, 126 μL, 0.252 mmol). The mixture wasstirred at 0° C. for 10 min before warming to rt and stirring for 3 h.The reaction mixture was quenched by saturated aqueous ammonium chloridesolution (15 mL) and diluted with ethyl acetate (25 mL). The organiclayer was washed with 0.5% HCl (15 mL) and brine (10 mL), dried overNa₂SO₄, filtered and concentrated by rotary evaporation to afford 56 mg(˜100% yield) of(R)—N—((R)-2-(4-(ethylthio)phenyl)-1-hydroxypropan-2-yl)-2-methylpropane-2-sulfinamide,which was used without further purification. LCMS t_(R)=1.35 min in 2min chromatography, MS (ESI) m/z 316 [M+H]⁺.

Step 5: 2-amino-2-(4-(ethylthio)phenyl)propan-1-ol

To a solution of(R)—N—((R)-2-(4-(ethylthio)phenyl)-1-hydroxypropan-2-yl)-2-methylpropane-2-sulfinamide(53 mg, 0.168 mmol) in methanol (3 mL) was added HCl solution (4.0 M indioxane, 3 mL). The mixture was stirred at rt for 3 h. The mixture wasconcentrated to afford crude 2-amino-2-(4-(ethylthio)phenyl)propan-1-ol,which was used without further purification. LCMS t_(R)=0.66 min in 2min chromatography, MS (ESI) m/z 195 [M−NH₃+H]⁺.

Preparation B5: (R)-2-amino-2-(5-(ethylsulfonyl)pyridin-2-yl)ethanol

Step 1: 2-bromo-5-(ethylthio)pyridine

To a mixture of 2-bromo-5-fluoropyridine (6.28 g, 35.66 mmol) inanhydrous DMF (60 mL) was added sodium ethanethiolate (3 g, 35.66 mmol).The mixture was stirred at 100° C. for 3 h. TLC (petroleum ether/ethylacetate 10/1) showed that the starting material was not consumedcompletely. Additional sodium ethanethiolate (0.9 g, 9.56 mmol) wasadded to the mixture. The mixture was stirred at 100° C. for 12 h. Themixture was quenched with H₂O (150 mL) and extracted with ethyl acetate(3×150 mL). The combined organic layers were washed with brine (400 mL),dried over anhydrous sodium sulfate, filtered and concentrated underreduced pressure. The residue was purified by silica gel chromatography(eluting with petroleum ether/ethyl acetate 80/1) to afford2-bromo-5-(ethylthio)pyridine (7.0 g, 90%) as a colorless oil.

LC-MS t_(R)=0.717 min in 5-95AB_1.5 min chromatography (Welch MerckRP-18e 25-2 mm), MS (ESI) m/z 217.6 [M+H]⁺.

Step 2:(R)—N—((R)-2-((tert-butyldimethylsilyl)oxy)-1-(5-(ethylthio)pyridin-2-yl)ethyl)-2-methylpropane-2-sulfinamide

To a solution of toluene (60 mL) was added n-BuLi (10.6 mL, 26.48 mmol,2.5 M in hexanes) dropwise at −78° C.; the internal temperature did notexceed −50° C. A solution of 2-bromo-5-(ethylthio)pyridine (3.85 g,17.65 mmol) in toluene (10 mL) was then added to the reaction mixture at−78° C.; the internal temperature did not exceed −65° C. The mixture wasstirred at −78° C. for 1 h. A solution of(R,E)-N-(2-((tert-butyldimethylsilyl)oxy)ethylidene)-2-methylpropane-2-sulfinamide(4.90 g, 17.65 mmol) in toluene (10 mL) was added to the reactionmixture at −78° C.; the internal temperature did not exceed −60° C. Themixture was stirred at −78° C. for another 2 h. The mixture was quenchedwith brine (150 mL) at −78° C. and extracted with ethyl acetate (3×150mL). The combined organic layers were washed with brine (400 mL), driedover anhydrous sodium sulfate, filtered and concentrated under reducedpressure. The residue was purified by silica gel chromatography (elutingwith petroleum ether/ethyl acetate 10/1 to 3/1) to afford(R)—N—((R)-2-((tert-butyldimethylsilyl)oxy)-1-(5-(ethylthio)pyridin-2-yl)ethyl)-2-methylpropane-2-sulfinamide(3.0 g, 41%) as a pale yellow oil. LC-MS t_(R)=1.014 min in 5-95AB_1.5min chromatography (Welch Merck RP-18e 25-2 mm), MS (ESI) m/z 417.2[M+H]⁺.

Step 3: (R)-2-amino-2-(5-(ethylthio)pyridin-2-yl)ethanol

Procedure same as that for (R)-2-amino-2-(4-(ethylthio)phenyl)ethanolwith(R)—N—((R)-2-((tert-butyldimethylsilyl)oxy)-1-(5-(ethylthio)pyridin-2-yl)ethyl)-2-methylpropane-2-sulfinamideas the starting material.

Step 4: (R)-2-amino-2-(5-(ethylsulfonyl)pyridin-2-yl)ethanol

Procedure same as that for(R)-2-amino-2-(4-(ethylsulfonyl)phenyl)ethanol with(R)-2-amino-2-(5-(ethylthio)pyridin-2-yl)ethanol as the startingmaterial. ¹H NMR (CD₃OD, 400 MHz): δ 9.08 (s, 1H), 8.35 (dd, J=2.0, 8.4Hz, 1H), 7.79 (d, J=8.4 Hz, 1H), 4.70 (t, J=5.6 Hz, 1H), 4.03 (dd,J=4.8, 12.0 Hz, 1H), 3.91 (dd, J=4.8, 11.6 Hz, 1H), 3.29 (q, J=7.2 Hz,2H), 1.25 (t, J=7.2 Hz, 3H).

Preparation B6: (R)-2-amino-2-(4-(methylsulfonyl)phenyl)ethanol

The compound was prepared analogously to(R)-2-amino-2-(4-(methylsulfonyl)phenyl)ethanol (B1).

Preparation B7: (R)-2-amino-2-(5-(methylsulfonyl)pyridin-2-yl)ethanol

The compound was prepared analogously to(R)-2-amino-2-(5-(ethylsulfonyl)pyridin-2-yl)ethanol (B5).

Preparation C1: trans-4-(trifluoromethyl)cyclohexanecarbaldehyde

Step 1: (trans-4-(trifluoromethyl)cyclohexyl)methanol

To a mixture of lithium aluminum hydride (11.6 g, 0.306 mol) inanhydrous THF (350 mL) was added a solution oftrans-4-(trifluoromethyl)cyclohexanecarboxylic acid (30 g, 0.153 mol) inanhydrous THF (50 mL) at 0° C. dropwise. The mixture was stirred at 0°C. for 2 h. TLC (petroleum ether:ethyl acetate=10:1) showed no startingmaterial remaining. The mixture was quenched with water (12 mL), 15%aqueous NaOH solution (24 mL) and H₂O (12 mL) successively. The mixturewas filtered and the filtrate was concentrated under vacuum to give(trans-4-(trifluoromethyl)cyclohexyl)methanol (24 g, 86%) as a liquid.¹H NMR (CDCl₃, 400 MHz): δ 3.49-3.50 (d, J=6.0 Hz, 2H), 1.91-2.07 (m,4H), 1.50-1.57 (m, 1H), 1.32-1.36 (m, 2H), 0.98-1.05 (m, 2H).

Step 2: trans-4-(trifluoromethyl)cyclohexanecarbaldehyde

To a mixture of oxalyl chloride (24.96 g, 13.84 mL, 197.7 mmol) inCH₂Cl₂ (250 mL) was added dropwise DMSO (20.72 g, 28 mL, 395.4 mmol) at−65° C. The mixture was stirred at −65° C. for 30 min(trans-4-(trifluoromethyl)cyclohexyl)methanol (12 g, 65.9 mmol)dissolved in CH₂Cl₂ (50 mL) was added dropwise at −65° C. and themixture was stirred at −65° C. for another 30 min Triethylamine (66.4 g,91.2 mL, 659 mmol) was added dropwise below −65° C. The mixture wasstirred at −65° C. for 30 min, then stirred at rt for 1.5 h. The mixturewas quenched with water (200 mL) and separated. The aqueous layer wasextracted with CH₂Cl₂ (2×300 mL). The combined organic layers werewashed with water (200 mL) and brine (200 mL), dried over anhydroussodium sulfate, filtered and concentrated under vacuum. The residue waspurified by silica gel chromatography (eluting with petroleumether:ethyl acetate=10:1) to givetrans-4-(trifluoromethyl)cyclohexanecarbaldehyde (8.9 g, 75%) as aslight yellow oil. ¹H NMR (CDCl₃, 400 MHz): δ 9.70 (s, 1H), 2.16-2.65(m, 3H), 2.04-2.12 (m, 3H), 1.00-1.39 (m, 4H).

Preparation C2: 6-(trifluoromethyl)tetrahydro-2H-pyran-3-carbaldehyde

Step 1: ethyl 2-(((1,1,1-trifluoropent-4-en-2-yl)oxy)methyl)acrylate

To a solution of 1,1,1-trifluoropent-4-en-2-ol (6.7 g, 48 mmol) inanhydrous (dried with CaH₂) DMF (85 mL) was added sodium hydride (2.3 g,57 mmol, 60% in mineral oil) in portions at 0° C. The mixture wasstirred at 0° C. for 30 min, then ethyl 2-(bromomethyl)acrylate (9.2 g,48 mmol) was added dropwise to the resulting mixture via syringe at 0°C. After addition, the mixture was stirred at rt for 2 h. TLC analysis(eluting with petroleum ether:ethyl acetate=10:1) showed that thestarting material was consumed. The reaction was quenched with water (50mL) at 0° C. and the aqueous layer was extracted with ethyl acetate(3×50 mL). The combined organic layers were washed successively withwater (3×50 mL) and brine (50 mL), dried over anhydrous sodium sulfate,filtered and concentrated under reduced pressure. The crude residue waspurified by silica gel chromatography (eluting with petroleumether/ethyl acetate: gradient from 100/1 to 50/1) to afford ethyl2-(((1,1,1-trifluoropent-4-en-2-yl)oxy)methyl)acrylate (6.6 g, 55%) as apale yellow oil. ¹H NMR (CDCl₃ 400 MHz): δ 6.31 (s, 1H), 5.89 (s, 1H),5.85-5.74 (m, 1H), 5.23-5.07 (m, 2H), 4.52-4.43 (m, 1H), 4.38-4.15 (m,3H), 3.82-3.68 (m, 1H), 2.50-2.35 (m, 2H), 1.38-1.20 (m, 3H).

Step 2: ethyl 6-(trifluoromethyl)-5,6-dihydro-2H-pyran-3-carboxylate

To a solution of ethyl2-(((1,1,1-trifluoropent-4-en-2-yl)oxy)methyl)acrylate (6.6 g, 26.2mmol) in anhydrous CH₂Cl₂ (2.6 L) was added Grubbs II catalyst (2.2 g,2.62 mmol) under N₂. The mixture was stirred at rt for 3 h. TLC analysis(eluting with petroleum ether:ethyl acetate=10:1) showed that thereaction was complete. Water (2 L) was added to the mixture to quenchthe reaction. After partition, the organic layer was washed successivelywith water (3×2 L) then brine (2 L), dried over anhydrous sodiumsulfate, filtered and concentrated under reduced pressure. The residuewas purified by silica gel chromatography (eluting with petroleumether/ethyl acetate: gradient from 100/1 to 80/1) to afford ethyl6-(trifluoromethyl)-5,6-dihydro-2H-pyran-3-carboxylate (4.83 g, 82%) asa pale yellow oil. ¹H NMR (CDCl₃ 400 MHz): δ 7.01 (d, J=2.8 Hz, 1H),4.63-4.58 (m, 1H), 4.40-4.33 (m, 1H), 4.20 (q, J=7.2 Hz, 2H), 3.95-3.84(m, 1H), 2.57-2.46 (m, 1H), 2.41-2.32 (m, 1H), 1.28 (t, J=7.2 Hz, 3H).

Step 3: ethyl 6-(trifluoromethyl)tetrahydro-2H-pyran-3-carboxylate

To a solution of ethyl6-(trifluoromethyl)-5,6-dihydro-2H-pyran-3-carboxylate (4.83 g, 22 mmol)in anhydrous THF (130 mL) was added dry Pd(OH)₂ on carbon (2.7 g, 10%w/w). The mixture was stirred at rt for 16 h under H₂ (30 psi). TLCanalysis (eluting with petroleum ether/ethyl acetate=10/1) showed thatmost of the starting material was not consumed. The mixture wasfiltered, then the filtrate was concentrated under reduced pressure anddissolved into anhydrous THF (60 mL). Dry Pd(OH)₂ on carbon (2.7 g, 10%w/w) was added to the mixture. The mixture was stirred at rt for 28 hunder H₂ (30 psi). TLC analysis (eluting with petroleum ether/ethylacetate=10/1) showed that the starting material was consumed. Themixture was filtered and the filtrate was concentrated under reducedpressure to afford crude ethyl6-(trifluoromethyl)tetrahydro-2H-pyran-3-carboxylate (3.4 g, 70%) as acolorless oil, which was used for the next step directly without furtherpurification. ¹H NMR (CDCl₃ 400 MHz): δ 4.50 (d, J=11.6 Hz, 1H), 4.18(q, J=7.2 Hz, 2H), 3.80-3.68 (m, 1H), 3.66 (d, J=3.2, 11.6 Hz, 1H),2.55-2.49 (m, 1H), 2.43-2.35 (m, 1H), 1.95-1.81 (m, 1H), 1.75-1.65 (m,2H), 1.25 (t, J=7.2 Hz, 3H).

Step 4: 6-(trifluoromethyl)tetrahydro-2H-pyran-3-carboxylic acid

To a solution of crude ethyl6-(trifluoromethyl)tetrahydro-2H-pyran-3-carboxylate (2.0 g, 8.8 mmol)in THF (24 mL), EtOH (12 mL) was added 1 N aqueous NaOH solution (12mL). The mixture was stirred at rt for 3 h. TLC analysis (eluting withpetroleum ether:ethyl acetate=10:1) showed that the reaction wascomplete. The mixture was added to water (20 mL) and concentrated underreduced pressure to remove the organic solvent. The residue was washedwith MTBE (20 mL) and adjusted to pH=4-5 with 1 N HCl solution. Then,the aqueous layer was extracted with EtOAc (3×20 mL). The combinedorganic layers were washed with brine (20 mL), dried over anhydroussodium sulfate, filtered and concentrated under reduced pressure toafford crude 6-(trifluoromethyl)tetrahydro-2H-pyran-3-carboxylic acid(1.72 g, 98%) as a pale yellow oil, which was used for the next stepdirectly without further purification.

The ratio of cis:trans isomers was ˜2:1 based on ¹H NMR and ¹⁹F NMRanalysis. ¹H NMR (CDCl₃ 400 MHz): δ 8.56 (br s, 1H), 4.47 (d, J=12.0 Hz,0.68H), 4.25 (d, J=12.0 Hz, 0.32H), 3.76-3.62 (m, 1.68H), 3.47 (t,J=11.2 Hz, 0.32H), 2.71-2.61 (m, 0.32H), 2.58-2.51 (m, 0.68H), 2.38-2.22(m, 1H), 1.88-1.80 (m, 1H), 1.75-1.60 (m, 2H).

Step 5: 6-(trifluoromethyl)tetrahydro-2H-pyran-3-carboxylic acid

To a solution of crude6-(trifluoromethyl)tetrahydro-2H-pyran-3-carboxylic acid (1.72 g, 8.69mmol) was added a 2 N aqueous NaOH solution (76 mL). The mixture wasstirred in sealed tube at 100° C. for 84 h. The mixture was diluted withwater (20 mL) and washed with MTBE (50 mL). The aqueous layer wasadjusted to pH=4-5 with 1 N HCl solution and extracted with EtOAc (3×50mL). The combined organic layers were washed with brine (50 mL), driedover anhydrous sodium sulfate, filtered and concentrated under reducedpressure to afford crude6-(trifluoromethyl)tetrahydro-2H-pyran-3-carboxylic acid (1.60 g, 93%)as a pale yellow oil, which was used for the next step directly withoutfurther purification.

The ratio of cis:trans was ˜1:3 based on ¹H NMR and ¹⁹F NMR analysis. ¹HNMR (CDCl₃ 400 MHz): δ 4.54 (d, J=12.0 Hz, 0.25H), 4.32 (dd, J=2.8, 11.6Hz, 0.75H), 3.83-3.68 (m, 1.25H), 3.52 (t, J=11.2 Hz, 0.75H), 2.75-2.58(m, 1H), 2.45-2.30 (m, 1H), 1.95-1.85 (m, 1H), 1.83-1.63 (m, 2H).

Step 6:N-methoxy-N-methyl-6-(trifluoromethyl)tetrahydro-2H-pyran-3-carboxamide

To a solution of crude6-(trifluoromethyl)tetrahydro-2H-pyran-3-carboxylic acid (1.0 g, 5.01mmol) (˜1:3 cis:trans ratio of isomers) in anhydrous CH₂Cl₂ (60 mL) wasadded N,O-dimethylhydroxylamine hydrochloride (980 mg, 10.10 mmol), EDCI(1.93 g, 10.10 mmol), HOBt (1.36 g, 10.10 mmol), anddiisopropylethylamine (1.95 g, 15.15 mmol). The mixture was stirred atrt for 16 h. The mixture was diluted with water (60 mL) and extractedwith CH₂Cl₂ (3×60 mL). The combined organic layers were washed withbrine (60 mL), dried over anhydrous sodium sulfate, filtered andconcentrated under reduced pressure. The residue was purified by silicagel chromatography (eluting with petroleum ether/ethyl acetate: gradientfrom 30/1 to 15/1) to affordN-methoxy-N-methyl-6-(trifluoromethyl)tetrahydro-2H-pyran-3-carboxamide(1.05 g, 87%) as a pale yellow oil.

The ratio of cis:trans was ˜1:3 based on ¹H NMR and ¹⁹F NMR analysis. ¹HNMR (CDCl₃ 400 MHz): δ 4.30-4.24 (m, 0.25H), 4.22-4.15 (m, 0.75H),3.90-3.68 (m, 4H), 3.62-3.52 (m, 1H), 3.24-3.14 (m, 2H), 3.10-2.98 (m,1H), 2.14-2.04 (m, 1H), 1.95-1.80 (m, 2H), 1.80-1.65 (m, 2H).

Step 7: 6-(trifluoromethyl)tetrahydro-2H-pyran-3-carbaldehyde

To a solution ofN-methoxy-N-methyl-6-(trifluoromethyl)tetrahydro-2H-pyran-3-carboxamide(90 mg, 0.373 mmol) (˜1:3 cis:trans ratio of isomers) in anhydrous THF(5 mL) was added lithium aluminum hydride (0.75 mL, 0.746 mmol, 1 M inTHF) dropwise at 0° C. under N₂. The mixture was stirred at 0° C. for 1h. TLC analysis (eluting with petroleum ether/ethyl acetate: 5/1) showedthat the reaction was complete. The mixture was quenched with saturatedaqueous sodium sulfate solution (1 mL) and filtered. The filtrate wasdiluted with CH₂Cl₂ (60 mL) and washed with water (60 mL), 10% aqueousHCl solution (0.5 M, 60 mL), saturated aqueous NaHCO₃ solution (60 mL)and water (60 mL). The organic layer was dried over anhydrous sodiumsulfate, filtered and concentrated under reduced pressure to affordcrude 6-(trifluoromethyl)tetrahydro-2H-pyran-3-carbaldehyde (60 mg, 88%)as a pale yellow oil, which was used for the next step directly withoutfurther purification. The ratio of cis:trans was ˜1:3 based on ¹H NMRand ¹⁹F NMR analysis.

Preparation C3:trans-5-(trifluoromethyl)tetrahydro-2H-pyran-2-carbaldehyde

Step 1: 2-((benzyloxy)methyl)-3,4-dihydro-2H-pyran

To a mixture of sodium hydride (15.8 g, 394.5 mmol, 60% in mineral oil)in anhydrous DMF (460 mL) was added dropwise(3,4-dihydro-2H-pyran-2-yl)methanol (30.0 g, 263 mmol) dissolved inanhydrous DMF (20 mL) at 0° C. slowly. The mixture was stirred at 0° C.for 30 min (Bromomethyl)benzene (49.4 g, 34.3 mL, 289 mmol) dissolved inanhydrous DMF (20 mL) was added dropwise and the mixture was stirred atrt for 18 h. TLC (petroleum ether) showed most of the(bromomethyl)benzene was consumed and a new spot was found. The mixturewas quenched with H₂O (200 mL) at 0° C. slowly, then extracted withethyl acetate (3×300 mL). The combined organic layers were washed withH₂O (3×300 mL) and brine (200 mL), dried over anhydrous sodium sulfate,filtered and concentrated under reduced pressure. The residue waspurified by silica gel chromatography on (eluting with petroleum ether)to give 2-((benzyloxy)methyl)-3,4-dihydro-2H-pyran (39.4 g, 73%) as acolorless oil. ¹H NMR (CDCl₃, 400 MHz): δ 7.27-7.35 (m, 5H), 6.39 (d,J=6.0 Hz, 1H), 4.68-4.69 (m, 1H), 4.53-4.63 (m, 2H), 4.00-4.03 (m, 1H),3.51-3.61 (m, 2H), 2.06-2.09 (m, 1H), 1.98-2.04 (m, 1H), 1.82-1.83 (m,1H), 1.67-1.70 (m, 1H).

Step 2: 6-((benzyloxy)methyl)tetrahydro-2H-pyran-3-ol

To a mixture of 2-((benzyloxy)methyl)-3,4-dihydro-2H-pyran (31 g, 152mmol) in anhydrous THF (400 mL) was added dropwise 9-BBN (730 mL, 365mmol, 0.5 M in THF) at 0° C. for 1 h. The mixture was stirred at rt for18 h. TLC (petroleum ether:ethyl acetate=5:1) showed the startingmaterial was consumed. 10% aqueous NaOH solution (200 mL) was added tothe mixture at 0° C., followed by 30% H₂O₂ (100 mL). The mixture wasstirred at 21-25° C. for 1 h. The reaction mixture was quenched withsaturated aqueous Na₂SO₃ solution (200 mL) at 0° C. and concentratedunder reduced pressure to remove THF. The residue was extracted withethyl acetate (2×200 mL). The combined organic layers were washed withH₂O (200 mL) and brine (200 mL), dried over anhydrous sodium sulfate,filtered and concentrated under reduced pressure. The residue waspurified by silica gel chromatography (eluting with petroleumether:ethyl acetate=2:1 to 1:1) to give6-((benzyloxy)methyl)tetrahydro-2H-pyran-3-ol (30.7 g, 91%) as acolorless oil. LC-MS t_(R)=0.869 min in 10-80AB_2 min chromatography(Xtimate ODS 2.1*30 mm, 3 um), MS (ESI) m/z 240.1 [M+18]⁺. ¹H NMR(CDCl₃, 400 MHz): δ 7.20-7.27 (m, 5H), 4.45-4.55 (m, 2H), 3.97-4.00 (m,1H), 3.60-3.65 (m, 1H), 3.34-3.43 (m, 3H), 3.05-3.11 (m, 1H), 2.13-2.14(m, 1H), 1.69-1.71 (m, 1H), 1.41-1.43 (m, 2H).

Step 3: 6-((benzyloxy)methyl)dihydro-2H-pyran-3(4H)-one

To a mixture of 6-((benzyloxy)methyl)tetrahydro-2H-pyran-3-ol (45.5 g,205 mmol) in anhydrous CH₂Cl₂ (500 mL) was added pyridiniumchlorochromate (88.4 g, 410 mmol) portionwise at 0° C. The mixture wasstirred at rt for 72 h. TLC (petroleum ether: ethyl acetate=3:1) showedthe starting material was consumed. The mixture was filtered throughKieselguhr and the filtrate was concentrated under reduced pressure. Theresidue was purified by silica gel chromatography (eluting withpetroleum ether:ethyl acetate=3:1 to 2:1) to give6-((benzyloxy)methyl)dihydro-2H-pyran-3(4H)-one (31 g, 69%) as an oil.LC-MS t_(R)=0.735 min in 10-80AB_2 min chromatography (Xtimate 2.1*30mm, 3 um), MS (ESI) m/z 256.1 [M+36]⁺. ¹H NMR (CDCl₃, 400 MHz): δ7.19-7.29 (m, 5H), 4.49-4.57 (m, 2H), 4.11-4.15 (m, 1H), 3.92-2.95 (m,1H), 3.85-3.91 (m, 1H), 3.47-3.54 (m, 2H), 2.53-2.54 (m, 1H), 2.40-2.44(m, 1H), 1.97-1.99 (m, 1H), 1.83-1.90 (m, 1H).

Step 4:6-((benzyloxy)methyl)-3-(trifluoromethyl)tetrahydro-2H-pyran-3-ol

To a mixture of 6-((benzyloxy)methyl)dihydro-2H-pyran-3(4H)-one (31.0 g,141 mmol) and trimethyl(trifluoromethyl)silane (50.1 g, 353 mmol) inanhydrous THF (300 mL) was added dropwise tetrabutylammonium fluoride(3.1 mL, 1 M in THF) at 0° C. The mixture was stirred at rt for 2 h. TLC(petroleum ether:ethyl acetate=5:1) showed the starting material wasconsumed. HCl solution (340 mL, v:v=1:1) was added to the mixture at 0°C., then stirring continued at rt for 18 h. TLC (petroleum ether:ethylacetate=5:1) showed the reaction was complete. The mixture wasconcentrated under reduced pressure to remove THF. The residue wasextracted with ethyl acetate (3×200 mL). The combined organic layerswere washed with H₂O (100 mL,) and brine (100 mL), dried over anhydroussodium sulfate, filtered and concentrated under reduced pressure. Theresidue was purified by silica gel chromatography (eluting withpetroleum ether:ethyl acetate=5:1) to give6-((benzyloxy)methyl)-3-(trifluoromethyl)tetrahydro-2H-pyran-3-ol (10.0g, 25%) as a colorless oil. LC-MS t_(R)=1.041 min in 10-80AB_2 minchromatography (Xtimate ODS 2.1*30 mm, 3 um), MS (ESI) m/z 308.1[M+18]⁺. ¹H NMR (CDCl₃, 400 MHz): δ 7.22-7.30 (m, 5H), 4.45-4.55 (m,2H), 4.09-4.13 (m, 1H), 3.60-3.62 (m, 1H), 3.47-3.49 (m, 1H), 3.32-3.41(m, 2H), 2.19-2.22 (m, 1H), 2.10 (brs, 1H), 1.62-1.69 (m, 4H). SFCt_(R)=4.512 and 4.857 min in 15 min chromatography (Column:AD-H_3_5_40_2.35 ML), ee=10.12%.

Step 5:6-((benzyloxy)methyl)-3-(trifluoromethyl)tetrahydro-2H-pyran-3-yl ethyloxalate

To a mixture of6-((benzyloxy)methyl)-3-(trifluoromethyl)tetrahydro-2H-pyran-3-ol (10.0g, 34.4 mmol) and pyridine (8.16 g, 8.3 mL, 103.2 mmol) in anhydrousCH₂Cl₂ (150 mL) was added dropwise ethyl chlorooxoacetate (9.41 g, 68.8mmol) at 0° C. The mixture was stirred at rt for 20 h. TLC (petroleumether:ethyl acetate=5:1) showed most of the starting material wasconsumed. The mixture was washed with 1 N HCl (50 mL) and brine (50 mL).The organic layer was dried over anhydrous sodium sulfate, filtered andconcentrated under reduced pressure. The residue was purified by silicagel chromatography (eluting with petroleum ether:ethyl acetate=8:1) togive 6-((benzyloxy)methyl)-3-(trifluoromethyl)tetrahydro-2H-pyran-3-ylethyl oxalate (11 g, 82%) as a colorless oil. LC-MS t_(R)=1.225 min in10-80AB_2 min chromatography (Xtimate ODS 2.1*30 mm, 3 um), MS (ESI) m/z408.2 [M+18]⁺. ¹H NMR (CDCl₃, 400 MHz): δ 7.29-7.36 (m, 5H), 4.51-4.61(m, 2H), 4.47-4.48 (m, 1H), 4.35 (q, J=7.2 Hz, 2H), 4.00-4.01 (m, 1H),3.60-3.62 (m, 1H), 3.53-3.54 (m, 1H), 3.45-3.48 (m, 1H), 2.63-2.68 (m,1H), 2.34-2.35 (m, 1H), 1.74-1.78 (m, 2H), 139 (t, J=7.2 Hz, 3H).

Step 6:trans-2-((benzyloxy)methyl)-5-(trifluoromethyl)tetrahydro-2H-pyran

To a mixture of6-((benzyloxy)methyl)-3-(trifluoromethyl)tetrahydro-2H-pyran-3-yl ethyloxalate (10.0 g, 25.6 mmol) in anhydrous toluene (600 mL) was addeddropwise AIBN (1.26 g, 7.68 mmol) and tributyltin hydride (15.05 g, 51.2mmol) dissolved in anhydrous toluene (200 mL) at 130° C. over 40 min.The mixture was stirred at 130° C. for 7 h. LCMS showed the reaction wascomplete. The mixture was concentrated under reduced pressure. Theresidue was dissolved in ethyl acetate (200 mL) and aqueous KF solution(100 mL) and filtered. The filtrate was separated. The aqueous phase wasextracted with ethyl acetate (2×200 mL). The combined organic layerswere washed with brine (100 mL), dried over anhydrous sodium sulfate,filtered and concentrated under reduced pressure. The residue waspurified by silica gel chromatography (eluting with petroleumether:ethyl acetate=10:1 to 8:1) to givetrans-2-((benzyloxy)methyl)-5-(trifluoromethyl)tetrahydro-2H-pyran (lesspolar peak, 3.3 g, 47%) andcis-2-((benzyloxy)methyl)-5-(trifluoromethyl)tetrahydro-2H-pyran (morepolar peak, 1.55 g, 22%) as oil.trans-2-((benzyloxy)methyl)-5-(trifluoromethyl)tetrahydro-2H-pyran:LC-MS t_(R)=3.978 min in 10-80AB_7 min chromatography (Xtimate ODS2.1*30 mm, 3 um), MS (ESI) m/z 292.0 [M+18]⁺. ¹H NMR (CDCl₃, 400 MHz): δ7.29-7.35 (m, 5H), 4.57 (q, J=12.0 Hz, 2H), 4.17-4.20 (m, 1H), 3.41-3.54(m, 4H), 2.37-2.38 (m, 1H), 2.06-2.10 (m, 1H), 1.70-1.74 (m, 1H),1.30-1.42 (m, 2H). SFC t_(R)=3.237 and 3.528 min in 12 minchromatography (Column: OJ-H_3_5_40_2.5 ML), ee=5.62%. SFC t_(R)=3.158and 3.375 min in 12 min chromatography (Column: OJ-H_5_5_40_2.5 ML),ee=0.85%.cis-2-((benzyloxy)methyl)-5-(trifluoromethyl)tetrahydro-2H-pyran: LC-MSt_(R)=3.739 min in 10-80AB_7 min chromatography (Xtimate ODS 2.1*30 mm,3 um), MS (ESI) m/z 292.0 [M+18]⁺. ¹H NMR (CDCl₃ 400 MHz): δ 7.21-7.30(m, 5H), 4.50 (q, J=12.0 Hz, 2H), 4.14-4.18 (m, 1H), 3.57-3.58 (m, 2H),3.45-3.49 (m, 1H), 3.33-3.36 (m, 1H), 2.03-2.11 (m, 2H), 1.19-1.77 (m,3H). SFC t_(R)=3.304 and 4.188 min in 12 min chromatography (Column:OJ-H_3_5_40_2.5 ML), ee=9.85%. SFC t_(R)=3.312 and 4.273 min in 12 minchromatography (Column: OD-H_5_5_40_2.5 ML), ee=18.6%.

Step 7: trans-(5-(trifluoromethyl)tetrahydro-2H-pyran-2-yl)methanol

A mixture oftrans-2-((benzyloxy)methyl)-5-(trifluoromethyl)tetrahydro-2H-pyran (1.0g, 3.6 mmol), dry Pd/C (250 mg, 10% Pd) and HCl (3 mL, 4 N in MeOH) inMeOH (20 mL) was stirred at rt for 18 h under H₂ (15 psi). TLC(petroleum ether:ethyl acetate=10:1) showed the starting material wasconsumed. The mixture was filtered and the filtrate was concentratedunder reduced pressure. The residue was purified by silica gelchromatography (eluting with petroleum ether:ethyl acetate=5:2 to 1:1)to give trans-(5-(trifluoromethyl)tetrahydro-2H-pyran-2-yl)methanol (550mg, 82%) as a slight yellow oil. ¹H NMR (CDCl₃, 400 MHz): δ 4.10-4.12(m, 1H), 3.35-3.59 (m, 4H), 2.29-2.30 (m, 1H), 2.01-2.05 (m, 2H),1.58-1.61 (m, 2H), 1.33-1.36 (m, 1H).

Step 8: trans-5-(trifluoromethyl)tetrahydro-2H-pyran-2-carbaldehyde

To a mixture of oxalyl chloride (1.14 g, 0.77 mL, 8.97 mmol) inanhydrous CH₂Cl₂ (15 mL) was added dropwise DMSO (1.4 g, 1.27 mL, 17.94mmol) at −78° C. The mixture was stirred at −78° C. for 30 minTrans-(5-(trifluoromethyl)tetrahydro-2H-pyran-2-yl)methanol (550 mg,2.99 mmol) dissolved in CH₂Cl₂ (5 mL) was added dropwise at −78° C. andthe mixture was stirred at −78° C. for another 2 h. Triethylamine (3.03g, 4.2 mL, 29.9 mmol) was added dropwise at −78° C. and the mixture wasstirred at −78° C. for 30 min, then rt for 1 h. The mixture was addedwith H₂O (20 mL), extracted with CH₂Cl₂ (3×20 mL). The combined organiclayers were dried over anhydrous sodium sulfate, filtered andconcentrated under reduced pressure. The residue was purified by silicagel chromatography (eluting with petroleum ether:ethyl acetate=3:1) togive trans-5-(trifluoromethyl)tetrahydro-2H-pyran-2-carbaldehyde (450mg, 70% purity, 83%) as a yellow oil. ¹H NMR (CDCl₃, 400 MHz): δ 9.55(s, 1H), 4.06-4.19 (m, 2H), 3.35-3.46 (m, 1H), 2.33-2.35 (m, 4H),2.10-2.14 (m, 1H).

Preparation of Compounds of Formula I

Compounds of Formula (I) were prepared according to the generalprocedures outlined below.

Example 1(S)—N—((R)-1-(4-(ethylsulfonyl)phenyl)-2-hydroxyethyl)-7-isopropyl-6-((trans-4-(trifluoromethyl)cyclohexyl)methyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-3-carboxamide

Step 1: (S)-tert-butyl3-(((R)-1-(4-(ethylsulfonyl)phenyl)-2-hydroxyethyl)carbamoyl)-7-isopropyl-5H-pyrrolo[3,4-b]pyridine-6(7H)-carboxylate

A mixture of(S)-6-(tert-butoxycarbonyl)-7-isopropyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-3-carboxylicacid (11 g, 36 mmol), (R)-2-amino-2-(4-(ethylsulfonyl)phenyl)ethanol(11.5 g, 43.2 mmol), HATU (16.4 g, 43.2 mmol) and triethylamine (21.9 g,30 mL, 216 mmol) in DMF (350 mL) was stirred at rt for 2 h. The reactionmixture was diluted with H₂O (140 mL) and extracted with ethyl acetate(3×140 mL). The combined organic layer was washed with water (3×150 mL)and brine (150 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated under vacuum. The residue was purified by silica gelchromatography (eluting with petroleum ether:ethyl acetate=1:3) toafford (S)-tert-butyl3-(((R)-1-(4-(ethylsulfonyl)phenyl)-2-hydroxyethyl)carbamoyl)-7-isopropyl-5H-pyrrolo[3,4-b]pyridine-6(7H)-carboxylate(6.1 g, 33%) as a light green solid. LC-MS t_(R)=0.845 min in 5-95AB_1.5min chromatography (MK RP18e 25-2 mm), MS (ESI) m/z 518.3 [M+H]⁺. ¹H NMR(CDCl₃, 400 MHz): δ 8.87 (s, 1H), 7.95 (s, 1H), 7.81-7.83 (d, J=8.4 Hz,2H), 7.53-7.55 (d, J=8.4 Hz, 2H), 7.16 (s, 1H), 5.26-5.28 (m, 1H),4.88-4.96 (m, 1H), 4.71-4.80 (m, 1H), 4.45-4.47 (m, 1H), 4.03-4.06 (m,1H), 3.94-3.98 (m, 1H), 3.01-3.06 (q, J=7.6 Hz, 2H), 2.49 (brs, 1H),2.35 (brs, 1H), 1.46 (s, 9H), 1.19-1.24 (t, J=7.6 Hz, 3H), 0.92-1.02 (m,3H), 0.67-0.72 (m, 3H). Isomer SFC t_(R)=8.073 and 9.821 min in 15 minchromatography (AD-H_5_5_40_2.35 ML), ee=96.91%.

Step 2:(S)—N—((R)-1-(4-(ethylsulfonyl)phenyl)-2-hydroxyethyl)-7-isopropyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-3-carboxamide

To a solution of (S)-tert-butyl3-(((R)-1-(4-(ethylsulfonyl)phenyl)-2-hydroxyethyl)carbamoyl)-7-isopropyl-5H-pyrrolo[3,4-b]pyridine-6(7H)-carboxylate(6.6 g, 12.8 mmol) in CH₂Cl₂ (200 mL) was added HCl (60 mL, 4 N indioxane) at 0° C. The mixture was stirred at rt for 4 h. LCMS showed nostarting material remaining. The mixture was concentrated under vacuum.The residue was adjusted to pH=9-10 with 10% NaOH solution, thenextracted with ethyl acetate (4×200 mL). The combined organic layerswere dried over anhydrous Na₂SO₄, filtered and concentrated underreduced pressure to afford(S)—N—((R)-1-(4-(ethylsulfonyl)phenyl)-2-hydroxyethyl)-7-isopropyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-3-carboxamide(5.3 g, 99.6%) as a light yellow solid, which was used for the next stepdirectly without further purification. LC-MS t_(R)=0.341 min in5-95AB_1.5 min chromatography (MK RP18e 25-2 mm), MS (ESI) m/z 418.1[M+H]⁺. ¹H NMR (CDCl₃, 400 MHz): δ 8.88 (s, 1H), 7.94 (s, 1H), 7.84-7.86(d, J=8.4 Hz, 2H), 7.57-7.59 (d, J=8.4 Hz, 2H), 7.28 (s, 1H), 5.29-5.33(m, 1H), 4.31 (s, 1H), 4.23 (s, 2H), 4.08-4.14 (m, 2H), 4.00-4.07 (m,1H), 3.06-3.11 (q, J=7.2 Hz, 2H), 2.28-2.31 (m, 1H), 1.24-1.29 (t, J=7.6Hz, 3H), 1.06-1.08 (d, J=7.2 Hz, 3H), 0.75-0.77 (d, J=6.4 Hz, 3H).Isomer SFC t_(R)=6.964, 7.904 and 9.124 min in 12 min chromatography(AD-3_B2_5_40_25 ML), ee=96.88%.

Step 3:(S)—N—((R)-1-(4-(ethylsulfonyl)phenyl)-2-hydroxyethyl)-7-isopropyl-6-((trans-4-(trifluoromethyl)cyclohexyl)methyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-3-carboxamide

To a mixture of(S)—N—((R)-1-(4-(ethylsulfonyl)phenyl)-2-hydroxyethyl)-7-isopropyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-3-carboxamide(5.3 g, 12.7 mmol) and trans-4-(trifluoromethyl)cyclohexanecarbaldehyde(4.58 g, 25.4 mmol) in anhydrous MeOH (100 mL) was added acetic aciddropwise until the pH was between 6 and 7. Sodium cyanoborohydride (3.19g, 50.8 mmol) was added portionwise at rt. The mixture was heated to 70°C. and stirred for 1 h. The mixture was cooled to rt and quenched withsaturated aqueous sodium bicarbonate (150 mL), then extracted with ethylacetate (3×200 mL). The combined organic layers were dried overanhydrous Na₂SO₄, filtered and concentrated under reduced pressure. Theresidue was purified by silica gel chromatography (eluting with ethylacetate) to give the product (6.63 g, 90%) as a light green solid, whichwas purified by SFC separation and acid (HCl) preparative HPLC twice togive(S)—N—((R)-1-(4-(ethylsulfonyl)phenyl)-2-hydroxyethyl)-7-isopropyl-6-((trans-4-(trifluoromethyl)cyclohexyl)methyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-3-carboxamide(46) (3551.7 mg, 53%) as a light yellow solid. LC-MS t_(R)=0.634 min in5-95AB_1.5 min chromatography (MK RP-18e 25-2 mm), MS (ESI) adz 582.1[M+H]⁺. ¹H NMR (CD₃OD, 400 MHz): δ 9.12-9.13 (d, J=2.0 Hz, 1H),9.31-9.32 (d, J=1.6 Hz, 1H), 7.91-7.93 (dd, J=6.8, 1.6 Hz, 2H),7.71-7.73 (d, J=8.0 Hz, 2H), 5.30-5.33 (t, J=6.4 Hz, 1H), 5.16-5.19 (d,J=15.2 Hz, 1H), 4.87-4.89 (m, 1H), 4.70-4.74 (d, J=15.2 Hz, 1H),3.93-3.95 (d, J=6.4 Hz, 2H), 3.30-3.35 (m, 2H), 3.19-3.25 (q, J=7.6 Hz,2H), 2.54-2.56 (m, 1H), 2.25-2.27 (m, 1H), 2.03-2.08 (m, 5H), 1.45-1.48(m, 2H), 1.33-1.35 (m, 4H), 1.23-1.27 (m, 4H), 1.11-1.13 (t, J=6.8 Hz,3H). ¹⁹F NMR (CD₃OD, 400 MHz): δ −75.39. Isomer SFC t_(R)=7.559 min in12 min chromatography (Column: AD-3_B2_5_40_25 ML) ee=100%. HClpreparative HPLC method; Mobile phase A: water with 0.05% HCl; Mobilephase B: CH₃CN. Flow rate: 90 mL/min Detection: UV 220 nm/254 nm Column:Phenomenex Synergi C18 250*50 mm*10 um. Column temperature: 30° C. Timein min: % A:% B; 0.00:87:13, 30.0:57:43; 30.20:0:100; 35.00:0:100.

Example 2(S)-7-ethyl-N—((R)-1-(4-(ethylsulfonyl)phenyl)-2-hydroxyethyl)-6-((trans-4-(trifluoromethyl)cyclohexyl)methyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-3-carboxamide

Step 1: (S)-tert-butyl7-ethyl-3-(((R)-1-(4-(ethylsulfonyl)phenyl)-2-hydroxyethyl)carbamoyl)-5H-pyrrolo[3,4-b]pyridine-6(7H)-carboxylate

A mixture of(S)-6-(tert-butoxycarbonyl)-7-ethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-3-carboxylicacid (8 g, 27.4 mmol), HATU (12.5 g, 32.9 mmol) and triethylamine (8.32g, 11.5 mL, 82.2 mmol) in DMF (120 mL) was stirred at rt for 0.5 h.(R)-2-amino-2-(4-(ethylsulfonyl)phenyl)ethanol (6.9 g, 30.1 mmol)dissolved in DMF (30 mL) was added dropwise to the mixture at 0° C. Themixture was stirred at rt for 2 h. LCMS showed no starting materialremaining. The reaction mixture was diluted with water (100 mL) andextracted with ethyl acetate (3×200 mL). The combined organic layerswere washed with water (3×100 mL) and brine (100 mL), dried overanhydrous Na₂SO₄, filtered and concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography (eluting withpetroleum ether:ethyl acetate=1:6 to 1:8) to give (S)-tert-butyl7-ethyl-3-(((R)-1-(4-(ethylsulfonyl)phenyl)-2-hydroxyethyl)carbamoyl)-5H-pyrrolo[3,4-b]pyridine-6(7H)-carboxylate(9.0 g, 65%) as a yellow solid. ¹H NMR (CDCl₃, 400 MHz): δ 8.96 (s, 1H),8.01 (s, 1H), 7.88-7.90 (d, J=8.0 Hz, 2H), 7.60-7.62 (d, J=8.4 Hz, 2H),7.29-7.30 (m, 1H), 5.32-5.35 (m, 1H), 5.04-5.13 (m, 1H), 4.76-4.82 (m,1H), 4.55-4.59 (m, 1H), 4.00-4.13 (m, 2H), 3.08-3.13 (q, J=7.6 Hz, 2H),2.19-2.22 (m, 2H), 1.53 (s, 9H), 1.28-1.30 (q, J=7.6 Hz, 3H), 0.65-0.68(q, J=7.2 Hz, 3H). LC-MS t_(R)=0.702 min in 5-95AB_1.5 minchromatography (MERCK RP-18e 25-2 mm), MS (ESI) m/z 504.0 [M+H]⁺.

Step 2:(S)-7-ethyl-N—((R)-1-(4-(ethylsulfonyl)phenyl)-2-hydroxyethyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-3-carboxamide

To a solution of (S)-tert-butyl7-ethyl-3-(((R)-1-(4-(ethylsulfonyl)phenyl)-2-hydroxyethyl)carbamoyl)-5H-pyrrolo[3,4-b]pyridine-6(7H)-carboxylate(9.0 g, 17.9 mmol) in CH₂Cl₂ (100 mL) was added dropwise HCl (30 mL, 4 Nin dioxane) at 0° C. The mixture was stirred at rt for 2 h. TLC(petroleum ether:ethyl acetate=1:3) showed no starting materialremaining. The mixture was concentrated under reduced pressure. Theresidue was basified to pH=9-10 with 10% aqueous NaOH solution, thenextracted with ethyl acetate (5×200 mL). The combined organic layerswere dried over anhydrous sodium sulfate, filtered and concentratedunder reduced pressure to afford(S)-7-ethyl-N—((R)-1-(4-(ethylsulfonyl)phenyl)-2-hydroxyethyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-3-carboxamide(7.2 g, 100%) as a yellow-red solid, which was used for the next stepdirectly without further purification.

Step 3:(S)-7-ethyl-N—((R)-1-(4-(ethylsulfonyl)phenyl)-2-hydroxyethyl)-6-((trans-4-(trifluoromethyl)cyclohexyl)methyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-3-carboxamide

To a mixture of(S)-7-ethyl-N—((R)-1-(4-(ethylsulfonyl)phenyl)-2-hydroxyethyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-3-carboxamide(7.2 g, 17.8 mmol) and trans-4-(trifluoromethyl)cyclohexanecarbaldehyde(4.81 g, 26.7 mmol) in anhydrous MeOH (100 mL) was added acetic aciddropwise until the pH was between 6 and 7. Sodium cyanoborohydride (4.47g, 71.2 mmol) was added portionwise at rt. The mixture was heated to 70°C. and stirred for 1 h. The mixture was cooled to rt and quenched withsaturated aqueous sodium bicarbonate (150 mL), then extracted with ethylacetate (2×150 mL). The combined organic layers were dried overanhydrous Na₂SO₄, filtered and concentrated under reduced pressure. Theresidue was purified by silica gel chromatography (eluting with ethylacetate), then purified further by SFC separation (AD-H) and acidic(HCl) preparative HPLC to give(S)-7-ethyl-N—((R)-1-(4-(ethylsulfonyl)phenyl)-2-hydroxyethyl)-6-((trans-4-(trifluoromethyl)cyclohexyl)methyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-3-carboxamide(41) (total 4.5 g, HCl salt, 46%) as a light yellow solid. LC-MSt_(R)=0.662 min in 5-95AB_1.5 min chromatography (RP-18e 25-2 mm), MS(ESI) m/z 568.0 [M+H]⁺. ¹H NMR (CD₃OD, 400 MHz): δ 9.07 (s, 1H), 8.27(s, 1H), 7.88-7.90 (d, J=8.0 Hz, 2H), 7.67-7.69 (d, J=8.0 Hz, 2H),5.26-5.29 (t, J=6.0 Hz, 1H), 5.06-5.10 (m, 2H), 4.70-4.80 (m, 1H),3.90-3.91 (d, J=6.4 Hz, 2H), 3.30-3.43 (m, 2H), 3.16-3.21 (q, J=7.2 Hz,2H), 1.97-2.22 (m, 8H), 1.18-1.46 (m, 10H). ¹⁹F NMR (CD₃OD, 400 MHz): δ−75.39. HCl preparative HPLC method Mobile phase A: water with 0.05%HCl; Mobile phase B: CH₃CN. Flow rate: 80 mL/min Detection: UV 220nm/254 nm Column: Phenomenex Gemini C18 250*50 mm*Sum. Columntemperature: 30° C. Time in min: % A:% B; 0.00:70:30; 8.00:45:55;8.20:0:100; 10.00:0:100.

Example 3 Crystalline mesylate of(S)-7-ethyl-N—((R)-1-(4-(ethylsulfonyl)phenyl)-2-hydroxyethyl)-6-((trans-4-(trifluoromethyl)cyclohexyl)methyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-3-carboxamide,compound (41) as crystalline mono mesylate

(S)-7-ethyl-N—((R)-1-(4-(ethylsulfonyl)phenyl)-2-hydroxyethyl)-6-((trans-4-(trifluoromethyl)cyclohexyl)methyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-3-carboxamideHCl salt (993.2 mg, 1.64 mmol) was dissolved in CH₂Cl₂ (60 mL), andwashed with 1 N NaOH (40 mL). The aqueous layer was then back-extractedwith CH₂Cl₂ (4×5 mL). The combined CH₂Cl₂ layers were dried over Na₂SO₄,filtered, and concentrated under reduced pressure. The free amine (915.1mg, 1.61 mmol) was redissolved in EtOH (10 mL) and cooled to 0° C.Methanesulfonic acid (Aldrich, 99.5%, 171.3 mg, 1.1 equiv) was addedwith stirring to obtain a light yellow solution. Several crystal seedswere added to the solution, which was then stirred at rt overnight(white solid came out within 5 min) Crystals were collected byfiltration, yielding 985.3 mg (92%) of white solid after pumping underhigh vacuum for 4 h to afford(S)-7-ethyl-N—((R)-1-(4-(ethylsulfonyl)phenyl)-2-hydroxyethyl)-6-((trans-4-(trifluoromethyl)cyclohexyl)methyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-3-carboxamidemono mesylate. LC-MS (2 min method): t_(R)=0.93 min ¹H NMR (CD₃OD, 400MHz): δ 9.06 (d, J=7.2 Hz, 1H), 9.01 (s, 1H), 8.19 (s, 1H), 7.83 (d,J=8.4 Hz, 2H), 7.62 (d, J=8.4 Hz, 2H), 5.22 (dd, J=7.2, 6.0 Hz, 1H),5.99 (d, J=14.8 Hz, 1H), 4.94 (m, 1H), 4.61 (d, J=14.8 Hz, 1H), 3.84 (d,J=6.0 Hz, 1H), 3.41 (m, 2H), 3.12 (q, J=7.2 Hz, 2H), 2.61 (s, 3H),2.20-1.80 (m, 8H), 1.44-1.32 (m, 2H), 1.26 (t, J=7.2 Hz, 3H), 1.20 (m,2H), 1.14 (t, J=7.2 Hz, 3H). ¹⁹F NMR (CD₃OD, 400 MHz): δ −75.50 (d, J=94Hz).

Crystal seeds were obtained in the following manner to a solution of(S)-7-ethyl-N—((R)-1-(4-(ethylsulfonyl)phenyl)-2-hydroxyethyl)-6-((trans-4-(trifluoromethyl)cyclohexyl)methyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-3-carboxamide(59.7 mg, 0.11 mmol) in ethyl acetate (0.5 mL) was added methanesulfonicacid (19.8 mg, 1.95 eq) dropwise. The salt oiled out. After decantingthe top layer of ethyl acetate, the residue was dried over vacuum toremove any residual ethyl acetate. The residue was then redissolved inEtOH (˜5 mL) by warming the solution up to give a clear solution.Crystals crashed out after standing at rt overnight (17.5 mg, 25%).

The following compounds in Table 1 were prepared according to themethods described herein. Where designated, an “*” indicates thatalthough a single diastereomer was isolated, the absolute configurationabout these positions was not fully characterized, however the relativestereochemistry at one of the designated positions to the otherdesignated position is as shown. Accordingly, groups (pairs) ofcompounds exist (e.g., compounds 1 and 4; 2 and 5; 3 and 6; 10 and 11;14 and 15; 18 and 21; 29 and 30; 34 and 42; and 39 and 42) where asingle diastereomer was isolated and tested, but where the absolutestereochemistry about the “*” is arbitrarily defined. For example incompound 1, the trifluoromethyl group is trans relative to itsconnection to the dihydropyrrolopyridine core.

TABLE 1 LC/ MS (tR, Inter- meth- mediate Cpd. od, ¹⁹F NMR Compo- No.Structure m/z) ¹H NMR (CD₃OD) (CD₃OD) nents 1

0.731 (1.5 min) 585.1 [M + H]⁺ 9.13 (s, 1H), 9.04 (d, J = 2.0 Hz, 1H),8.34 (d, J = 2.0 Hz, 1H), 8.33 (d, J = 8.0 Hz, 1H), 7.79 (d, J = 8.0 Hz,1H), 5.40 (t, J = 6.0 Hz, 1H), 5.18-5.12 (m, 1H), 4.76-4.65 (m, 2H),4.29 (d, J = 10.0 Hz, 1H), 4.09-4.04 (m, 2H), 3.91-3.85 (m, 1H),3.41-3.35 (m, 3H), 3.30 (q, J = 7.2 Hz, 2H), 2.62-2.53 (m, 1H),2.32-2.18 (m, 2H), 1.94-1.89 (m, 1H), 1.73-1.63 (m, 1H), 1.52-1.41 (m,1H), 1.33 (d, A1, B5, C2 J = 6.8 Hz, 3H), 1.26 (t, J = 7.2 Hz, 3H), 1.09(broad s, 3H). 2

0.629 (1.5 min) 584.1 [M + H]⁺ 9.12 (s, 1H), 8.28 (s, 1H), 7.90 (d, J =8.0 Hz, 2H), 7.70 (d, J = 8.0 Hz, 2H), 5.30 (t, J = 6.4 Hz, 1H),5.15-5.06 (m, 1H), 4.80-4.68 (m, 2H), 4.26 (d, J = 10.0 Hz, 1H), 3.92(d, J = 6.4 Hz, 2H), 3.89 (m, 1H), 3.41-3.32 (m, 3H), 3.20 (q, J = 7.2Hz, 2H), 2.66-2.52 (m, 1H), 2.38-2.17 (m, 2H), 1.92 (d, J = 12.4 Hz,1H), 1.76-1.67 (m, 1H), 1.52-1.44 (m, 1H), 1.32 (d, J = 6.8 Hz, 3H), A1,B1, C2 1.21 (t, J = 7.2 Hz, 3H), 1.08 (broad s, 3H). 3

0.627 (1.5 min) 571.2 [M + H]⁺ 9.12 (s, 1H), 9.06 (s, 1H), 8.35 (s, 1H),8.34 (d, J = 8.0 Hz, 1H), 7.81 (d, J = 8.4 Hz, 1H), 5.41 (t, J = 6.0 Hz,1H), 5.16-5.06 (m, 1H), 4.86-4.74 (m, 2H), 4.34-4.29 (m, 1H), 4.09-4.04(m, 2H), 3.94-3.86 (m, 1H), 3.53-3.40 (m, 2H), 3.32 (q, J = 7.2 Hz, 2H),2.38-2.18 (m, 4H), 1.96 (d, J = 12.8 Hz, 1H), 1.76-1.69 (m, 1H),1.58-1.49 (m, 1H), 1.33 (broad s, 3H), 1.28 (t, −80.56 A2, B5, C2 J =7.2 Hz, 3H). 4

0.741 (1.5 min) 585.1 [M + H]⁺ 9.13 (s, 1H), 9.04 (d, J = 2.0 Hz, 1H),8.34 (d, J = 2.4 Hz, 1H), 8.33 (d, J = 8.4 Hz, 1H), 7.79 (d, J = 8.4 Hz,1H), 5.40 (t, J = 6.0 Hz, 1H), 5.20-5.09 (m, 1H), 4.81-4.72 (m, 2H),4.27 (d, J = 11.2 Hz, 1H), 4.07-4.03 (m, 2H), 3.92-3.85 (m, 1H),3.41-3.35 (m, 3H), 3.29 (q, J = 7.2 Hz, 2H), 2.60-2.52 (m, 1H),2.34-2.19 (m, 2H), 1.93 (d, J = 12.8 Hz, 1H), 1.72-1.64 A1, B5, C2 (m,1H), 1.58-1.46 (m, 1H), 1.32 (d, J = 7.2 Hz, 3H), 1.26 (t, J = 7.2 Hz,3H), 1.07 (broad s, 3H). 5

0.637 (1.5 min) 584.1 [M + H]⁺ 9.12 (s, 1H), 8.29 (s, 1H), 7.90 (d, J =8.4 Hz, 2H), 7.70 (d, J = 8.4 Hz, 2H), 5.30 (t, J = 6.0 Hz, 1H),5.16-5.05 (m, 1H), 4.83-4.70 (m, 2H), 4.26 (d, J = 14.8 Hz, 1H), 3.92(d, J = 6.4 Hz, 2H), 3.91-3.86 (m, 1H), 3.40-3.32 (m, 3H), 3.20 (q, J =7.2 Hz, 2H), 2.58-2.47 (m, 1H), 2.33-2.16 (m, 2H), 1.93 (d, J = 12.8 Hz,1H), 1.73-1.62 (m, 1H), 1.58- 1.47 (m, 1H), 1.32 (d, J = A1, B1, C2 6.8Hz, 3H), 1.21 (t, J = 7.2 Hz, 3H), 1.06 (broad s, 3H). 6

0.780 (2.0 min) 571.2 [M + H]⁺ 9.12 (d, J = 2.0 Hz, 1H), 9.06 (d, J =2.4 Hz, 1H), 8.34 (dd, J = 2.0 Hz, 8.4 Hz, 2H), 7.81 (d, J = 8.4 Hz,1H), 5.41 (t, J = 6.4 Hz, 1H), 5.15-5.04 (m, 1H), 4.83-4.72 (m, 2H),4.24 (d, J = 10.4 Hz, 1H), 4.09-4.05 (m, 2H), 3.96-3.89 (m, 1H),3.44-3.36 (m, 2H), 3.32 (q, J = 7.2 Hz, 2H), 2.36-2.24 (m, 4H), 1.95 (d,J = 10.4 Hz, 1H), 1.76- 1.69 (m, 1H), 1.54-1.46 (m, −80.57 A2, B5, C21H), 1.35 (broad s, 3H), 1.28 (t, J = 7.2 Hz, 3H). 7

1.06 (2.0 min) 596.6 [M + H]⁺ 9.11 (s, 1H), 8.73 (s, 1H), 8.26 (s, 1H),7.91 (d, J = 8.4 Hz, 2H), 7.74 (d, J = 8.8 Hz, 2H), 5.01 (m, 1H), 3.90(m, 2H), 3.23 (q, J = 7.2 Hz, 2H), 2.57 (m, 1H), 2.21 (m, 1H), 2.13-1.94(m, 6H), 1.87 (s, 3H), 1.83 (m, 1H), 1.47 (m, 2H), 1.35 (d, J = 7.2 Hz,3H), 1.26 (t, J = 7.2 Hz, 3H), 1.09 (s, 3H). −75.4 A1, B4, C1 Amidecoupling of A1 and B4 was per- formed prior to treat- ment with oxone. 8

0.634 (1.5 min) 568.1 [M + H]⁺ 9.13 (s, 1H), 8.28 (s, 1H), 7.96 (d, J =8.4 Hz, 2H), 7.71 (d, J = 8.4 Hz, 2H), 5.31 (t, J = 6.4 Hz, 1H),5.16-5.07 (m, 1H), 4.85-4.74 (m, 2H), 3.93 (d, J = 7.2 Hz, 2H),3.58-3.48 (m, 3H), 3.13 (s, 3H), 2.58-2.44 (m, 1H), 2.36-2.24 (m, 2H),1.87-1.66 (m, 9H), 1.31 (broad s, 3H), 1.08 (broad s, 3H). A1, B6, C1 9

1.04 (2.0 min) 596.6 [M + H]⁺ 9.05 (s, 1H), 8.66 (s, 1H), 8.20 (s, 1H),7.86 (d, J = 8.4 Hz, 2H), 7.69 (d, J = 8.8 Hz, 2H), 3.92 (m, 2H), 3.17(q, J = 7.6 Hz, 2H), 2.16 (m, 1H), 2.03 (m, 4H), 1.83 (s, 3H), 1.42 (m,2H), 1.28 (d, J = 7.2 Hz, 3H), 1.22 (t, J = 7.6 Hz, 3H), 1.04 (m, 3H).−75.4 A1, B4, C1 Amide coupling of A1 and B4 was per- formed prior totreat- ment with oxone. 10

0.641 (1.5 min) 570.2 [M + H]⁺ 9.10 (d, J = 1.6 Hz, 1H), 8.31 (s, 1H),7.92 (d, J = 8.4 Hz, 2H), 7.72 (d, J = 8.4 Hz, 2H), 5.31 (t, J = 6.4 Hz,1H), 5.20-5.10 (m, 1H), 4.83-4.73 (m, 2H), 4.34 (d, J = 10.0 Hz, 1H),3.94 (d, J = 6.4 Hz, 2H), 3.93 (m, 1H), 3.51 (broad s, 1H), 3.40-3.33(m, 2H), 3.21 (q, J = 7.2 Hz, 2H), 2.34-2.17 (m, 4H), 1.96 (d, J = 13.2Hz, 1H), 1.77- 1.66 (m, 1H), 1.63-1.47 (m, −80.56 A2, B1, C2 1H), 1.34(broad s, 3H), 1.23 (t, J = 7.2 Hz, 3H). 11

0.638 (1.5 min) 570.2 [M + H]⁺ 9.10 (s, 1H), 8.31 (s, 1H), 7.92 (d, J =8.4 Hz, 2H), 7.72 (d, J = 8.4 Hz, 2H), 5.31 (t, J = 6.4 Hz, 1H),5.14-5.04 (m, 1H), 4.84-4.73 (m, 2H), 4.25-4.18 (m, 1H), 3.94 (d, J =6.4 Hz, 2H), 3.91 (m, 1H), 3.46-3.34 (m, 3H), 3.21 (q, J = 7.6 Hz, 2H),2.39-2.19 (m, 4H), 1.96 (d, J = 12.8 Hz, 1H), 1.78- 1.67 (m, 1H),1.56-1.46 (m, 1H), 1.35 (broad s, 3H), −80.57 A2, B1, C2 1.23 (t, J =7.6 Hz, 3H) 12

0.883 (2.0 min) 584.3 [M + H]⁺ 9.11 (s, 1H), 8.30 (s, 1H), 7.92 (dd, J =2.0 Hz, 8.4 Hz, 2H), 7.71 (d, J = 8.4 Hz, 2H), 5.31 (t, J = 6.4 Hz, 1H),5.20-5.08 (m, 2H), 4.79-4.69 (m, 1H), 4.25-4.08 (m, 2H), 3.94 (d, J =7.2 Hz, 2H), 3.60-3.38 (m, 4H), 3.22 (q, J = 7.6 Hz, 2H), 2.37-1.93 (m,6H), 1.53-1.42 (m, 2H), 1.32-1.25 (m, 2H), 1.23 (t, J = 7.6 Hz, 3H).−75.40 A8, B1, C1 13

0.883 (2.0 min) 584.3 [M + H]⁺ 9.12 (d, J = 2.0 Hz, 1H), 8.30 (s, 1H),7.93 (dd, J = 2.0 Hz, 8.4 Hz, 2H), 7.71 (d, J = 8.4 Hz, 2H), 5.31 (t, J= 6.4 Hz, 1H), 5.21-5.11 (m, 2H), 4.81-4.71 (m, 1H), 4.24-4.06 (m, 2H),3.94 (d, J = 7.2 Hz, 2H), 3.60-3.38 (m, 4H), 3.22 (q, J = 7.2 Hz, 2H),2.29-1.93 (m, 6H), 1.55-1.41 (m, 2H), 1.32-1.24 (m, 2H), 1.23 (t, J =7.2 Hz, 3H). −75.40 A8, B1, C1 14

0.664 (1.5 min) 584.1 [M + H]⁺ 9.08 (s, 1H), 8.24 (s, 1H), 7.92 (d, J =8.4 Hz, 2H), 7.71 (d, J = 8.4 Hz, 2H), 5.31 (t, J = 6.4 Hz, 1H),5.11-5.04 (m, 1H), 4.86-4.76 (m, 2H), 4.21 (d, J = 8.8 Hz, 1H), 3.94 (d,J = 7.2 Hz, 2H), 3.83-3.75 (m, 1H), 3.53-3.46 (m, 3H), 3.22 (q, J = 7.2Hz, 2H), 2.62-2.44 (m, 3H), 2.19-2.11 (m, 1H), 1.88-1.72 (m, 2H),1.53-1.44 (m, 2H), 1.34-1.25 (m, 1H), 1.23 (t, J = 7.2 Hz, 3H), −73.36A1, B1, C3 1.13-1.04 (m, 3H). 15

0.655 (1.5 min) 584.0 [M + H]⁺ 9.13 (s, 1H), 8.30 (s, 1H), 7.92 (d, J =8.4 Hz, 2H), 7.72 (d, J = 8.4 Hz, 2H), 5.32 (t, J = 6.4 Hz, 1H),5.15-5.08 (m, 1H), 4.84-4.74 (m, 2H), 4.30-4.21 (m, 1H), 3.98-3.90 (m,3H), 3.59-3.41 (m, 3H), 3.22 (q, J = 7.2 Hz, 2H), 2.63-2.44 (m, 2H),2.18-2.11 (m, 1H), 1.87-1.59 (m, 2H), 1.48-1.38 (m, 3H), 1.23 (t, J =7.2 Hz, 3H), 1.18-1.05 (m, 3H). −73.33 A1, B1, C3 16

0.641 (1.5 min) 555.0 [M + H]⁺ 9.10 (s, 1H), 9.08 (d, J = 2.4 Hz, 1H),8.33 (dd, J = 2.0 Hz, 8.4 Hz, 1H), 8.29 (s, 1H), 7.74 (d, J = 8.4 Hz,1H), 5.38 (t, J = 6.0 Hz, 1H), 5.08 (d, J = 14.8 Hz, 1H), 4.83-4.71 (m,2H), 4.07-4.03 (m, 2H), 3.49-3.33 (m, 2H), 3.20 (s, 3H), 2.24-1.93 (m,8H), 1.48-1.38 (m, 2H), 1.36-1.18 (m, 5H). −75.39 A2, B7, C1 17

0.811 (2.0 min) 570.2 [M + H]⁺ 9.12 (s, 1H), 8.30 (s, 1H), 7.92 (d, J =8.4 Hz, 2H), 7.71 (d, J = 8.4 Hz, 2H), 5.31 (t, J = 6.4 Hz, 1H),5.16-5.05 (m, 2H), 4.81-4.71 (m, 1H), 4.38-4.28 (m, 2H), 3.94 (d, J =7.2 Hz, 2H), 3.70-3.38 (m, 2H), 3.22 (q, J = 7.2 Hz, 2H), 2.29-1.96 (m,6H), 1.53-1.38 (m, 2H), 1.31-1.25 (m, 2H), 1.23 (t, J = 7.2 Hz, 3H).−75.40 A7, B1, C1 Removal of the TBS group was per- formed in the samestep as Boc depro- tection 18

0.655 (1.5 min) 584.0 [M + H]⁺ 9.10 (s, 1H), 8.27 (s, 1H), 7.90 (d, J =8.4 Hz, 2H), 7.70 (d, J = 8.4 Hz, 2H), 5.29 (t, J = 6.4 Hz, 1H),5.14-4.95 (m, 2H), 4.85-4.74 (m, 1H), 4.26 (d, J = 14.0 Hz, 2H), 3.96(broad s, 1H), 3.92 (d, J = 6.4 Hz, 2H), 3.74-3.53 (m, 3H), 3.20 (q, J =7.2 Hz, 2H), 2.55-2.36 (m, 2H), 2.20-1.95 (m, 2H), 1.62 (broad s, 2H),1.30 (d, J = 6.8 Hz, 3H), 1.21 (t, J = 7.2 Hz, 3H), 1.11 −68.553 A1, B1,C3 (broad s, 3H). 19

0.787 (1.5 min) 548.0 [M + H]⁺ 9.01 (s, 1H), 8.22 (s, 1H), 7.92 (d, J =8.4 Hz, 2H), 7.70 (d, J = 8.4 Hz, 2H), 5.29 (t, J = 6.4 Hz, 1H), 4.74(broad s, 1H), 4.36 (d, J = 14.4 Hz, 1H), 4.06 (d, J = 14.4 Hz, 1H),3.91 (d, J = 6.0 Hz, 2H), 3.54-3.39 (m, 3H), 3.22 (q, J = 7.2 Hz, 2H),3.20 (m, 1H), 1.23 (t, J = 7.2 Hz). −71.60 A5, B1 20

0.809 (2.0 min) 570.2 [M + H]⁺ 9.12 (s, 1H), 8.30 (s, 1H), 7.92 (d, J =8.4 Hz, 2H), 7.72 (d, J = 8.4 Hz, 2H), 5.32 (t, J = 6.4 Hz, 1H),5.18-5.05 (m, 2H), 4.85-4.81 (m, 1H), 4.38-4.28 (m, 2H), 3.94 (d, J =6.4 Hz, 2H), 3.64-3.35 (m, 2H), 3.22 (q, J = 7.2 Hz, 2H), 2.27-1.94 (m,6H), 1.52-1.42 (m, 2H), 1.31-1.25 (m, 2H), 1.23 (t, J = 7.2 Hz, 3H).−75.40 A7, B1, C1 Removal of the TBS group was per- formed in the samestep as Boc depro- tection 21

0.641 (1.5 min) 584.0 [M + H]⁺ 9.12 (s, 1H), 8.32 (s, 1H), 7.92 (d, J =8.4 Hz, 2H), 7.72 (d, J = 8.4 Hz, 2H), 5.31 (t, J = 6.4 Hz, 1H),5.13-4.94 (m, 2H), 4.85-4.76 (m, 1H), 4.29 (d, J = 12.0 Hz, 2H), 4.01(broad s, 1H), 3.94 (d, J = 6.0 Hz, 2H), 3.73-3.44 (m, 3H), 3.22 (q, J =7.6 Hz, 2H), 2.55-2.40 (m, 2H), 2.23-1.94 (m, 2H), 1.98 (broad s, 2H),1.31-1.25 (m, 3H), 1.23 (t, J = 7.6 Hz, 3H), 1.08 (broad s, 3H). −68.515A1, B1, C3 22

0.787 (1.5 min) 548.0 [M + H]⁺ 9.01 (s, 1H), 8.22 (s, 1H), 7.92 (d, J =8.4 Hz, 2H), 7.70 (d, J = 8.4 Hz, 2H), 5.29 (t, J = 6.4 Hz, 1H), 4.74(broad s, 1H), 4.36 (d, J = 14.4 Hz, 1H), 4.06 (d, J = 14.4 Hz, 1H),3.91 (d, J = 6.8 Hz, 2H), 3.54-3.42 (m, 3H), 3.22 (q, J = 7.2 Hz, 2H),3.20 (m, 1H), 1.23 (t, J = 7.2 Hz). −71.593 A5, B1 23

1.116 (2.0 min) 608.2 [M + H]⁺ 8.97 (d, J = 5.2 Hz, 1H), 8.21 (s, 1H),7.92 (d, J = 8.4 Hz, 2H), 7.71 (d, J = 8.4 Hz, 2H), 5.31 (t, J = 6.4 Hz,1H), 4.75-4.70 (m, 1H), 4.55 (d, J = 14.4 Hz, 1H), 3.95 (s, 1H), 3.93(d, J = 6.4 Hz, 2H), 3.22 (q, J = 7.6 Hz, 2H), 2.84 (d, J = 7.6 Hz, 2H),2.26-1.94 (m, 5H), 1.68-1.57 (m, 1H), 1.42-1.34 (m, 2H), 1.23 (t, J =7.6 Hz, 3H), 1.11-0.94 (m, 2H). −75.309, −75.491 A9, B1, C1 24

0.608 (1.5 min) 554.1 [M + H]⁺ 9.18 (d, J = 7.2 Hz, 1H), 9.09 (s, 1H),8.28 (s, 1H), 7.95 (d, J = 8.4 Hz, 2H), 7.69 (d, J = 8.4 Hz, 2H),5.32-5.27 (m, 1H), 5.09 (d, J = 14.4 Hz, 1H), 4.83-4.65 (m, 2H), 3.92(d, J = 6.8 Hz, 2H), 3.47-3.39 (m, 2H), 3.11 (s, 3H), 2.23-1.98 (m,10H), 1.48-1.32 (m, 5H). −75.39 A2, B6, C1 25

0.643 (1.5 min) 568.0 [M + H]⁺ 9.10 (s, 1H), 8.26 (s, 1H), 7.95 (d, J =8.8 Hz, 2H), 7.69 (d, J = 8.4 Hz, 2H), 5.29 (t, J = 6.4 Hz, 1H),5.15-5.10 (m, 1H), 4.72-4.65 (m, 1H), 3.92 (d, J = 6.4 Hz, 2H),3.35-3.30 (m, 3H), 3.11 (s, 3H), 2.55-2.45 (m, 1H), 2.19-1.95 (m, 6H),1.48-1.08 (m, 11H). A1, B6, C1 26

0.832 (2.0 min) 554.1 [M + H]⁺ 9.06-9.14 (m, 1H), 8.27-8.35 (m, 1H),7.86-7.96 (m, 2H), 7.67-7.76 (m, 2H), 5.27-5.35 (m, 1H), 5.04-5.15 (m,2H), 4.65-4.77 (m, 1H), 3.90-3.98 (m, 2H), 3.48-3.60 (m, 1H), 3.38-3.46(m, 1H), 3.14-3.27 (m, 2H), 1.95-2.28 (m, 7H), 1.83-1.92 (m, 2H),1.41-1.56 (m, 2H), 1.17-1.33 (m, 5H). −75.36 A6, B1, C1 27

0.869 (2.0 min) 638.3 [M + H]⁺ 9.16-9.18 (d, J = 7.2 Hz, 1H), 9.07 (s,1H), 8.25 (s, 1H), 7.87-7.89 (d, J = 8.0 Hz, 2H), 7.66-7.68 (d, J = 8.4Hz, 2H), 5.27-5.29 (m, 1H), 4.97-5.07 (m, 4H), 3.90-3.98 (m, 2H),3.88-3.89 (m, 2H), 3.43-3.49 (m, 4H), 3.17-3.21 (d, J = 7.6 Hz, 2H),1.71-2.13 (m, 13H), 0.96-1.45 (m, 9H). −75.39 A4, B1, C1 28

0.834 (2.0 min) 554.1 [M + H]⁺ 9.09-9.12 (m, 1H), 8.29-8.33 (m, 1H),7.89-7.95 (m, 2H), 7.68-7.75 (m, 2H), 5.28-5.35 (m, 1H), 5.06-5.14 (m,2H), 4.66-4.75 (m, 1H), 3.92-3.96 (d, J = 6.4 Hz, 2H), 3.51- 3.60 (m,1H), 3.38-3.45 (m, 1H), 3.18-3.25 (m, 2H), 1.94-2.30 (m, 7H), 1.85-1.91(m, 2H), 1.41-1.56 (m, 2H), 1.16-1.30 (m, 5H). −75.38 A6, B1, C1 29

0.644 (1.5 min) 596.1 [M + H]⁺ 8.86 (s, 1H), 8.61 (d, J = 8.4 Hz, 1H),8.07 (s, 1H), 7.84 (d, J = 8.4 Hz, 2H), 7.70 (d, J = 8.4 Hz, 2H),5.20-5.00 (m, 3H), 4.75-4.60 (m, 1H), 4.36 (q, J = 6.4 Hz, 1H),3.50-3.35 (m, 2H), 3.17 (q, J = 7.2 Hz, 2H), 2.55-2.40 (m, 1H),2.25-1.85 (m, 7H), 1.50-1.35 (m, 3H), 1.35- 1.00 (m, 12H). A1, B3, C1 30

0.644 (1.5 min) 596.2 [M + H]⁺ 8.87 (s, 1H), 8.65-8.58 (m, 1H), 8.06 (s,1H), 7.86 (d, J = 8.4 Hz, 2H), 7.71 (d, J = 8.4 Hz, 2H), 5.25-4.95 (m,3H), 4.75-4.60 (m, 1H), 4.37 (q, J = 6.4 Hz, 1H), 3.50- 3.35 (m, 2H),3.18 (q, J = 7.2 Hz, 2H), 2.55-2.43 (m, 1H), 2.25-1.90 (m, 7H),1.50-1.35 (m, 3H), 1.35- 1.00 (m, 12H). A1, B3, C1 31

0.609 (1.5 min) 624.1 [M + H]⁺ 9.14-9.15 (d, J = 1.6 Hz, 1H), 8.30 (s,1H), 7.91-7.95 (d, J = 6.4 Hz, 2H), 7.71- 7.73 (d, J = 8.0 Hz, 2H),5.05-5.35 (m, 2H), 4.73-4.77 (m, 2H), 3.91-4.08 (m, 4H), 3.42-3.50 (m,2H), 3.21-3.23 (d, J = 7.2 Hz, 2H), 1.69- 2.23 (m, 11H), 1.17-1.49 (m,9H). −75.407 A3, B1, C1 32

0.748 (1.5 min) 569.2 [M + H]⁺ 9.11-9.12 (d, J = 1.2 Hz 1H), 9.06-9.07(d, J = 2.4 Hz, 1H), 8.36-8.39 (m, 1H), 8.33 (s, 1H), 7.82-7.86 (d, J =8.4 Hz, 1H), 5.40-5.43 (t, J = 5.6 Hz, 1H), 5.11-5.15 (d, J = 14.4 Hz,1H), 4.75-4.90 (m, 2H), 4.07-4.11 (m, 2H), 3.35-3.44 (m, 4H), 2.01-2.28(m, 8H), 1.19-1.50 (m, 10H). −75.39 A2, B5, C1 33

0.647 (1.5 min) 569.1 [M + H]⁺ 9.12 (s, 1H), 9.08-9.09 (d, J = 1.2 Hz,1H), 8.40-8.42 (d, J = 8.0 Hz, 1H), 8.34 (s, 1H), 7.86-7.89 (d, J = 8.4Hz, 1H), 5.40-5.43 (t, J = 5.6 Hz, 1H), 5.12-5.16 (d, J = 14.8 Hz, 1H),4.84-4.90 (m, 2H), 4.08-4.10 (m, 2H), 3.35-3.44 (m, 4H), 2.05-2.28 (m,8H), 1.19-1.50 (m, 10H). −75.38 A2, B5, C1 34

0.574 (1.5 min) 480.0 [M + H]⁺ 9.14 (s, 1H), 8.30 (s, 1H), 7.93-7.91 (d,J = 8.4 Hz, 2H), 7.73-7.71 (d, J = 8.4 Hz, 2H), 7.47-7.36 (m, 5H),5.51-5.23 (m, 2H), 4.93-4.91 (m, 2H), 4.62-4.58 (m, 1H), 3.95-3.93 (d, J= 8.4 Hz, 2H), 3.92-3.89 (m, 1H), 3.33-3.32 (m, 1H), 3.25-3.19 (q, J =7.6 Hz, 2H), 2.87 (s, 3H), 1.25-1.21 (t, J = 7.2 Hz, 3H). A5, B1 35

0.578 (1.5 min) 480.0 [M + H]⁺ 9.14 (s, 1H), 8.30 (s, 1H), 7.93-7.91 (d,J = 8.4 Hz, 2H), 7.73-7.71 (d, J = 8.4 Hz, 2H), 7.47-7.36 (m, 5H),5.33-5.23 (m, 2H), 4.97-4.92 (m, 2H), 4.62-4.59 (m, 1H), 3.95-3.93 (d, J= 8.4 Hz, 2H), 3.92-3.89 (m, 1H), 3.33-3.32 (m, 1H), 3.25-3.19 (q, J =7.6 Hz, 2H), 2.87 (s, 3H), 1.25-1.21 (t, J = 7.2 Hz, 3H). A5, B1 36

0.617 (1.5 min) 583.1 [M + H]⁺ 9.11 (s, 1H), 9.02 (s, 1H), 8.35-8.26 (m,2H), 7.74 (d, J = 8.4 Hz, 1H), 5.38 (t, J = 6.0 Hz, 1H), 5.18-5.08 (m,1H), 5.05-4.94 (m, 1H), 4.80-4.67 (m, 1H), 4.08-4.01 (m, 2H), 3.55-3.45(m, 2H), 3.27 (q, J = 7.6 Hz, 2H), 2.56-2.47 (m, 1H), 2.37-2.23 (m, 2H),2.07-2.00 (m, 1H), 1.95-1.60 (m, 7H), 1.30 (d, J = 6.8 Hz, 3H), 1.24 (t,J = 7.6 Hz, 3H), 1.07 (d, J = 6.8 Hz, 3H). A1, B5, C1 37

0.660 (1.5 min) 630.1 [M + H]⁺ 9.15 (s, 1H), 8.32 (s, 1H), 7.94-7.92 (d,J = 8.4 Hz, 2H), 7.73-7.71 (d, J = 8.4 Hz, 2H), 7.54-7.41 (m, 5H),5.34-5.28 (m, 2H), 5.22-5.18 (d, J = 14.4 Hz, 1H), 4.71- 4.67 (d, J =14.4 Hz, 1H), 3.98-3.93 (m, 3H), 3.25-3.19 (m, 4H), 2.66-2.64 (m, 1H),2.05-1.90 (m, 4H), 1.71-1.68 (m, 2H), 1.36-1.29 (m, 2H), 1.25-121 (t, J= 7.2 Hz, 3H), 0.88-0.82 (m, 2H). −75.445 A5, B1, C1 38

0.745 (1.5 min) 568.3 [M + H]⁺ 9.11 (s, 1H), 8.29 (s, 1H), 7.90-7.94 (d,J = 8.4 Hz, 2H), 7.72 (d, J = 8.0 Hz, 2H), 5.28-5.35 (t, J = 6.4, Hz,2H), 5.04-5.15 (m, 1H), 4.68-4.83 (m, 2H), 3.91-3.96 (m, 2H), 3.37-3.53(m, 2H), 3.20-3.24 (d, J = 7.2 Hz, 2H), 1.96-2.28 (m, 8H), 1.20-1.50 (m,10H). −75.407 A2, B1, C1 39

0.631 (1.5 min) 596.1 [M + H]⁺ 9.10 (s, 1H), 9.04 (d, J = 8.0 Hz, 1H),8.26 (s, 1H), 7.89 (d, J = 8.0 Hz, 2H), 7.70 (d, J = 8.4 Hz, 2H),5.20-5.00 (m, 3H), 4.75-4.65 (m, 1H), 4.18 (t, J = 6.4 Hz, 1H),3.50-3.35 (m, 2H), 3.20 (q, J = 7.6 Hz, 2H), 2.60-2.45 (m, 1H),2.25-1.90 (m, 7H), 1.55-1.35 (m, 3H), 1.35-1.00 (m, 12H). A1, B2, C1 40

0.651 (1.5 min) 630.1 [M + H]⁺ 9.15 (s, 1H), 8.32 (s, 1H), 7.93-7.91 (d,J = 8.4 Hz, 2H), 7.73-7.71 (d, J = 8.4 Hz, 2H), 7.55-7.41 (m, 5H),5.34-5.28 (m, 2H), 5.22-5.18 (d, J = 14.8 Hz, 1H), 4.89- 4.86 (d, J =14.8 Hz, 1H), 3.98-3.93 (m, 3H), 3.25-3.19 (m, 4H), 2.66-2.60 (m, 1H),2.05-1.90 (m, 4H), 1.71-1.68 (m, 2H), 1.36-1.29 (m, 2H), 1.25-121 (t, J= 7.2 Hz, 3H), 0.88-0.82 (m, 2H). −75.445 A5, B1, C1 42

0.775 (1.5 min) 596.3 [M + H]⁺ 9.07 (s, 1H), 8.28 (s, 1H), 7.89 (d, J =8.4 Hz, 2H), 7.71 (d, J = 8.0 Hz, 2H), 5.25-5.07 (m, 3H), 4.75-4.65 (m,1H), 4.19 (t, J = 6.0 Hz, 1H), 3.45-3.35 (m, 2H), 3.19 (q, J = 7.2 Hz,2H), 2.60- 2.50 (m, 1H), 2.25-1.90 (m, 7H), 1.55-1.35 (m, 3H), 1.35-1.00(m, 12H). A1, B2, C1 43

0.718 (1.5 min) 558.4 [M + H]⁺ 9.20-9.14 (m, 1H), 9.10 (s, 1H), 8.25 (s,1H), 7.89 (d, J = 8.4 Hz, 2H), 7.68 (d, J = 8.0 Hz, 2H), 5.35-5.25 (m,1H), 5.11-5.04 (m, 1H), 4.75-4.64 (m, 2H), 3.95-3.85 (m, 2H), 3.54 (q, J= 7.2 Hz, 2H), 3.42-3.30 (m, 3H), 3.19 (q, J = 7.6 Hz, 2H), 2.55- 2.43(m, 1H), 2.18-2.07 (m, 2H), 2.01-1.86 (m, 3H), 1.29 (d, J = 6.8 Hz, 3H),1.28- 1.20 (m, 3H), 1.20 (t, J = 7.6 Hz, 3H), 1.17 (t, J = 7.2 Hz, A1,B1 3H), 1.07 (d, J = 6.8 Hz, 3H). 44

0.620 (1.5 min) 583.1 [M + H]⁺ 9.11 (s, 1H), 9.01 (s, 1H), 8.31-8.24 (m,2H), 7.73 (d, J = 8.4 Hz, 1H), 5.38 (t, J = 6.0 Hz, 1H), 5.13-5.06 (m,1H), 4.85-4.75 (m, 2H), 4.75-4.67 (m, 1H), 4.10-4.03 (m, 2H), 3.45-3.36(m, 1H), 3.30 (q, J = 7.6 Hz, 2H), 2.56-2.47 (m, 1H), 2.25-1.92 (m, 7H),1.52-1.37 (m, 2H), 1.30 (d, J = 6.8 Hz, 3H), 1.24 (t, J = 7.6 Hz, 3H),1.22-1.15 (m, 1H), 1.08 (d, J= 6.8 Hz, 3H). A1, B5, C1 45

0.625 (1.5 min) 583.1 [M + H]⁺ 9.11 (s, 1H), 9.03 (s, 1H), 8.35-8.25 (m,2H), 7.78 (d, J = 8.4 Hz, 1H), 5.39 (t, J = 6.0 Hz, 1H), 5.18-5.09 (m,1H), 4.88-4.81 (m, 2H), 4.75-4.65 (m, 1H), 4.10-4.03 (m, 2H), 3.45-3.36(m, 1H), 3.32 (q, J = 7.6 Hz, 2H), 2.56-2.47 (m, 1H), 2.25-1.92 (m, 7H),1.52-1.37 (m, 2H), 1.30 (d, J = 6.8 Hz, 3H), 1.24 (t, J = 7.6 Hz, 3H),1.22-1.15 (m, 1H), 1.08 (d, J = 6.8 Hz, 3H). A1, B5, C1 47

0.761 (1.5 min) 582.3 [M + H]⁺ 9.19-9.21 (d, J = 6.8 Hz, 1H), 9.12-9.13(d, J = 2.0 Hz, 1H), 8.30-8.31 (d, J = 2.0 Hz, 1H), 7.90-7.95 (m, 2H),7.71-7.73 (d, J = 8.0 Hz, 2H), 5.27-5.35 (m, 1H), 5.14-5.18 (d, J = 15.6Hz, 1H), 4.71-7.75 (d, J = 15.2 Hz, 1H), 3.91-3.96 (m, 2H), 3.34-3.47(m, 2H), 3.20-3.25 (q, J = 7.2 Hz, 1H), 2.54- 2.56 (m, 1H), 2.07 (m,6H), 1.08-1.52 (m, 14H). A1, B1, C1

Biological Assays

Radio-Ligand RORγ Binding Assay (Assay 1)

Compounds of the present invention were tested for ability to bind toRORγ in a cell-free competition assay with commercially availableradio-ligand (RL), 25-hydroxy[26,27-³H]-cholesterol (PerkinElmer, Cat. #NET674250UC), for a ligand binding site on a recombinant RORγ LigandBinding Domain (LBD) protein expressed as a6×His-Glutathione-S-Transferase (GST) fusion. The assay was performed in96-well SPA plates (PerkinElmer, Cat. #1450-401) in 50 mM HEPES buffer,pH 7.4, containing 150 mM NaCl, 5 mM MgCl₂, 10% (v/v) glycerol, 2 mMCHAPS, 0.5 mM β-octylglucopyranoside and 5 mM DTT. Tested compounds weredissolved in DMSO, and semi-log (3.162×) serial dilutions of thecompounds were prepared in the same solvent. Two μL of the DMSOsolutions were mixed with 28 μL of 8.6 nM25-hydroxy[26,27-³H]-cholesterol and 50 μL of 24 nM RORγ LBD. The platewas shaken at 700 rpm for 20 min and incubated for 10 min at rt, afterwhich 40 μL of poly-Lys YSi SPA beads (PerkinElmer, Cat. # RPNQ0010)were added to achieve 50 μg of the beads per well. The plate wasincubated on an orbital shaker for 20 min and then for 10 min withoutagitation at rt. SPA signal for tritium beta radiation was registered onPerkinElmer Microbeta plate reader. Percent inhibition values werecalculated based on the high signal obtained with DMSO control and thelow signal observed with 10 μM standard RORγ inverse agonist T0901317(SigmaAldrich, Cat. # T2320). The percent inhibition vs. concentrationdata were fit into a four-parameter model, and IC50 values werecalculated from the fit as the concentrations corresponding to theinflection points on the dose-response curves Inhibitory constants (Ki)were calculated using the following equation, where [RL] is theconcentration in the assay and K_(D) is a dissociation constant of25-hydroxy[26,27-³H]-cholesterol:

$K_{i} = \frac{I\; C_{50}}{\left( {1 + \frac{\lbrack{RL}\rbrack}{K_{D}}} \right).}$ROR

t 5×RORE Assay in Jurkat Cells (Assay 2)

Compounds of the present invention were tested for RORγ inverse agonistactivity in a cell-based, transcriptional activity assay. SecretedNanoluc® luciferase was used as a reporter for transcriptional activityof the full-length ROR

t in Jurkat cells (ATCC, Cat. # TIB-152). A reporter plasmid wasconstructed by inserting 5 repeats of the ROR Response Element (RORE)AAAGTAGGTCA (SEQ ID NO:1) into a commercially available promoterlessplasmid pNL1.3 [secNluc] (Promega, Cat. # N1021) using KpnI and HindIIIrestriction sites. The expression plasmid for ROR

t was purchased (GeneCopoeia, Cat. # EX-T6988-MO2). Jurkat cells (30million cells) were transfected with 11 μg of EX-T6988-MO2 and 26 μg ofthe reporter plasmid in OptiMEM® media using Lipofectamine® LTX andPlus™ reagents (Life Technologies, Cat. #15338-100). After 5-6 hrincubation at 37° C./5% CO₂, the cells were collected, resuspended inphenol-red free RPMI media containing 10% (v/v) dilapidated FBS(Hyclone, Cat. # SH30855.03) and dispensed into 96-well clear bottomtissue culture plates (CoStar, Cat. #3603), at 80,000 cells per well.Tested compounds were added to the cells in the same media (finalconcentration of DMSO was 0.1% (v/v)), and the plates were incubated at37° C./5% CO₂ for 16-18 hr. Luciferase activity in the conditionedsupernatants was determined with NanoGlo® assay reagents (Promega, Cat.#N1130). Percent inhibition values were calculated based on the fullyinhibited and non-inhibited (DMSO) controls, and the values wereregressed against concentrations of the tested compounds to derive IC50values using a four-parameter non-linear fitting model.

Human Whole Blood Assay (Assay 3)

Compounds of the invention were tested in the human whole blood assay tomeasure their effects on IL-17A production as determined by cytokinesecretion into 50% blood/media supernatant. Mixtures of sodiumheparinized whole blood (isolated from healthy human donors) and the Tcell activator CytoStim, in the presence or absence of compound, wereplated in sterilized, tissue culture-treated 24-well plates.Specifically, the mixtures in each well were as follows: (1) 500 μL ofwhole blood, (2) 250 μL of compound diluted into RPMI-1640 mediacontaining 10% HyClone™ FCS (Thermo Fisher Scientific, Waltham, Mass.),Gibco® Pen/Strep and Gibco® NEAA (Life Technologies, Grand Island,N.Y.), and (3) 250 μL of CytoStim (Miltenyi Biotech, Germany) diluted toa final concentration of 10 μL/mL in complete cell culture medium.

Mixtures were incubated at 37° C./5% CO₂ for 48 h, after which, 200 μLof clean supernatant (i.e., no red blood cells) from each well wastransferred to a well in a 96-well plate. IL-17A cytokine expression wasdetermined using 25 μL of the transferred supernatant diluted with 25 μLof Diluent 43 from the Human IL-17A V-PLEX™ kit (cat. # K151RFD-4, MesoScale Discovery, Rockville, Md.). The assay was performed according tothe manufacturer's instructions using included reagents. The IL-17AV-PLEX™ plates were read using the Meso Scale Discovery Imager (Model1200). The levels of IL-17A were extrapolated from a standard curveusing a four-parameter non-linear fitting model and expressed as pg/mL.These values were regressed against concentrations of the testedcompounds to derive IC₅₀ values using a four-parameter non-linearfitting model.

hERG Assay (Assay 4)

Compounds of the invention were tested in vitro against the hERG (humanether-à-go-go-related gene) potassium ion channel (a surrogate for IKr,the rapidly activating delayed rectifier cardiac potassium ion channel).

The buffer was HEPES-buffered physiological saline (HB-PS) solutioncomposed of: 137 mM NaCl, 4.0 mM KCl, 1.8 mM CaCl₂, 1 mM MgCl₂, 10 mMHEPES, 10 mM glucose, pH adjusted to 7.4 with NaOH, and 0.3% DMSO.Chemicals used in solution preparation were purchased from Sigma-Aldrich(St. Louis, Mo.), unless otherwise noted, and were of ACS reagent gradepurity or higher.

HEK (human embryonic kidney) 293 cells were stably transfected with hERGcDNA.

For the patch clamp experiment, onset and steady state inhibition ofhERG potassium current was measured using a pulse pattern with fixedamplitudes (depolarization: +20 mV for 2 s; repolarization: −50 mV for 2s) repeated at 10 s intervals from a holding potential of −80 mV. Peaktail current was measured during the 2 s step to −50 mV. A steady statewas maintained for at least 30 seconds before applying compound orpositive control (cisapride). Peak tail currents were measured until anew steady state was achieved.

Data acquisition and analyses were performed using the suite of pCLAMP®(ver. 8.2) programs (MDS Analytical Technologies, Sunnyvale, Calif.).Steady state was defined by the limiting constant rate of change withtime (linear time dependence). The steady state before and after eachcompound application was used to calculate the percentage of currentinhibited at each concentration.

Concentration-response data were fit to an equation of the followingform:% Inhibition={1−1/[1+([Test]/IC50)N]}*100

where [Test] was the compound concentration, IC50 was the compoundconcentration at half-maximal inhibition, N was the Hill coefficient,and % Inhibition was the percentage of current inhibited at eachcompound concentration. Nonlinear least squares fits were solved withthe Solver add-in for Excel 2003 (Microsoft, WA) and the IC50 wascalculated.

The results of assays 1 and 2 are shown in Table 2.

TABLE 2 RORγ RORγt5X Binding Ki IC50 Range* Compound Range* (nM) (nM) #(Assay 1) (Assay 2) 1 +++ +++ 2 +++ +++ 3 +++ 4 +++ +++ 5 +++ +++ 6 ++ 7+++ ++ 8 +++ + 9 ++ 10 +++ +++ 11 +++ +++ 12 ++ 13 +++ +++ 14 +++ +++ 15+++ +++ 16 ++ 17 + 18 +++ + 19 +++ ++ 20 ++ 21 +++ + 22 +++ +++ 23 ++++++ 24 +++ +++ 25 +++ +++ 26 +++ ++ 27 +++ +++ 28 + 29 ++ 30 ++ 31 ++++++ 32 ++ 33 +++ +++ 34 ++ 35 ++ 36 +++ + 37 +++ +++ 38 ++ 39 +++ +++ 40++ 41 +++ +++ 42 +++ +++ 43 +++ +++ 44 +++ +++ 45 +++ +++ 46 +++ +++ 47+++ +++ *+ means > 1000 nM; ++ means 100 nM − 1000 nM; +++ means < 100nM.

The results of assays 3 and 4 are shown in Table 3.

TABLE 3 hERG Assay 50% Human Whole (Compound at Blood Assay 3μM)Compound IC50, nM* % Inhibition Number (Assay 3) (Assay 4) 1 +++ 2 +++ 4+++ 5 +++ 10 +++ 14 +++ 25 ++ 3.2 33 +++ 29.1 39 ++ 32.7 41 +++ 7.7 42 +63.9 44 + 28.6 45 + 46 +++ 44.3 47 + *+ means > 200 nM; ++ means 100 nM− 200 nM; +++ means < 100 nM.

The results of assays 1 to 4 with comparator compounds are shown inTable 4.

TABLE 4 50% Human RORy Whole Binding RORyt5X Blood hERG Assay Ki IC50Assay (Compound Range^(A) Range^(A) IC50, at 3 μM) (nM) (nM) nM^(B) %Inhibition Comparator Compound (Assay 1) (Assay 2) (Assay 3) (Assay 4)

+++ +++ 57.0

+++ +++ + 45.4 ^(A)+ means >1000 nM; ++ means 100 nM-1000 nM; +++ means<100 nM. ^(B)+ means >200 nM; ++ means 100 nM-200 nM; +++ means <100 nM.

While we have described a number of embodiments of this invention, it isapparent that our basic examples may be altered to provide otherembodiments that utilize the compounds and methods of this invention.Therefore, it will be appreciated that the scope of this invention is tobe defined by the appended claims rather than by the specificembodiments that have been represented by way of example.

The contents of all references (including literature references, issuedpatents, published patent applications, and co-pending patentapplications) cited throughout this application are hereby expresslyincorporated herein in their entireties by reference. Unless otherwisedefined, all technical and scientific terms used herein are accorded themeaning commonly known to one with ordinary skill in the art.

The invention claimed is:
 1. A compound of the formula:

or a pharmaceutically acceptable salt thereof.
 2. A pharmaceuticalcomposition comprising a compound of the formula:

or a pharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier.
 3. A method of treating a disease or disorderselected from psoriasis, psoriatic arthritis (PsA), inflammatory boweldisease (IBD), rheumatoid arthritis, juvenile rheumatoid arthritis,systemic lupus erythematosus (SLE), multiple sclerosis, ankylosingspondylitis, and asthma in a subject, comprising administering to thesubject a therapeutically effective amount of a compound having theformula:

or a pharmaceutically acceptable salt thereof.
 4. The method of claim 3,wherein the disease or disorder is psoriatic arthritis (PsA).
 5. Themethod of claim 3, wherein the disease or disorder is ankylosingspondylitis.
 6. The method of claim 3, wherein the disease or disorderis psoriasis.